TW202207941A - Atr inhibitors for the treatment of cancer - Google Patents

Abstract

This specification discloses the use of an ATR inhibitor for the treatment of cancer in a particular subset of patients.

Description

用於治療癌症之ATR抑制劑ATR inhibitors for the treatment of cancer

本說明書關於ATR抑制劑在治療癌症中之用途，其特徵在於，將ATR抑制劑投與至之前已經接受免疫療法之患者，該ATR抑制劑係例如，4-{4-[(3R )-3-甲基𠰌啉-4-基]-6-[1-((R )-S -甲基磺醯胺基)環丙基]嘧啶-2-基}-1H-吡咯并[2,3-b]吡啶（AZD6738，賽拉雷澤替博（ceralasertib），下文稱為化合物 (I) 或其藥學上可接受的鹽）。說明書還關於治療之方法，該等方法包括將ATR抑制劑投與至之前已經接受免疫療法的患者；ATR抑制劑用於生產用於治療之前已經接受免疫療法的患者中的癌症的藥物之用途；包含一定量的多種ATR抑制劑的藥物組成物在癌症療法中之用途；以及包含此類藥物組成物的套組（kit）。

(I)The present specification relates to the use of an ATR inhibitor in the treatment of cancer, characterized in that the ATR inhibitor is administered to a patient who has previously received immunotherapy, the ATR inhibitor being, for example, 4-{4-[(3 R )- 3-Methylpyrin-4-yl]-6-[1-(( R ) -S -methylsulfonamido)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3 -b]pyridine (AZD6738, ceralasertib, hereinafter referred to as compound (I) or a pharmaceutically acceptable salt thereof). The instructions also pertain to methods of treatment comprising administering an ATR inhibitor to a patient who has previously received immunotherapy; use of the ATR inhibitor for the manufacture of a medicament for the treatment of cancer in a patient who has previously received immunotherapy; Use of pharmaceutical compositions comprising amounts of multiple ATR inhibitors in cancer therapy; and kits comprising such pharmaceutical compositions.

(I)

ATR係絲胺酸/蘇胺酸蛋白激酶並且是磷脂醯肌醇3-激酶相關激酶（PIKK）家族的成員。在正常的DNA複製過程中，ATR被募集在停止的複製叉處，該等複製叉如果不修復的話會發展成雙股斷裂。在單股DNA損害或雙股斷裂的切除後，ATR也被募集至覆蓋有複製蛋白A（RPA）的單股DNA。ATR的募集和激活導致細胞週期在S-階段停滯、同時DNA被修復並且停止的複製叉分解，或者核碎裂並且進入計劃性細胞死亡（細胞凋亡）。ATR is a serine/threonine protein kinase and is a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family. During normal DNA replication, ATR is recruited to stalled replication forks that, if not repaired, develop into double-strand breaks. ATR is also recruited to single-stranded DNA covered with replication protein A (RPA) following excision of single-stranded DNA damage or double-stranded breaks. Recruitment and activation of ATR results in cell cycle arrest in S-phase, the breakdown of replication forks, where DNA is repaired and stalled, or nuclear fragmentation and entry into programmed cell death (apoptosis).

因此，預期ATR抑制劑造成依賴ATR進行DNA修復的腫瘤細胞（例如，ATM-缺陷型腫瘤）之生長抑制。除了此類單療法活性，還預計ATR抑制劑（藉由抑制ATR-依賴性DNA修復過程）加強細胞毒性DNA損害劑的活性和放射療法療效（當它們聯合使用時）。Thus, ATR inhibitors are expected to cause growth inhibition of tumor cells that rely on ATR for DNA repair (eg, ATM-deficient tumors). In addition to such monotherapy activity, ATR inhibitors (by inhibiting ATR-dependent DNA repair processes) are also expected to potentiate the activity of cytotoxic DNA damaging agents and the efficacy of radiation therapy (when they are used in combination).

示例性ATR抑制劑包括AZD6738，一種相對於首先在WO 2011/154737中揭露的其他PIKK家族成員具有優良的選擇性的有效ATR抑制劑。該化合物正在被開發，作為患有依賴ATR功能進行DNA修復的疾病（例如絲胺酸/蘇胺酸-特異性蛋白激酶（ATM）缺陷型腫瘤）的患者之口服抗腫瘤劑。Exemplary ATR inhibitors include AZD6738, a potent ATR inhibitor with excellent selectivity over other PIKK family members first disclosed in WO 2011/154737. This compound is being developed as an oral antineoplastic agent for patients with diseases that depend on ATR function for DNA repair, such as serine/threonine-specific protein kinase (ATM)-deficient tumors.

ATR抑制劑正在被研究用於對抗各種形式的癌症，包括惡性黑色素瘤。黑色素瘤由皮膚中稱為黑素細胞的產色素細胞發展而來並且是皮膚癌中最危險之形式。在2015年，有310萬人患有活性黑色素瘤，這導致59,800人死亡（Vos等人，Lancet [柳葉刀]388 , 1545-1602）；而在2020年，美國癌症學會預計將局部診斷約100,000新病例，約7,000例死亡。ATR inhibitors are being studied to combat various forms of cancer, including malignant melanoma. Melanoma develops from pigment-producing cells in the skin called melanocytes and is the most dangerous form of skin cancer. In 2015, 3.1 million people had active melanoma, which resulted in 59,800 deaths (Vos et al., Lancet [Lancet] 388 , 1545-1602); in 2020, the American Cancer Society expects local diagnoses of approximately 100,000 New cases, about 7,000 deaths.

目前黑色素瘤的標準護理係基於一線免疫療法，例如使用免疫檢查點抑制劑，例如，納武單抗（nivolumab）或派姆單抗（pembrolizumab）。具有可訴性突變的患者（例如具有BRAF突變的患者）可以接受靶向藥劑。患者可以接受數種不同的免疫療法線，但是一旦它不再有效，標準的化學療法（像雙重卡鉑和紫杉醇或單藥劑紫杉醇）可用於繼續治療。然而，對化學療法的反應通常是差的，約20%患者反應於雙重化學療法並且僅約5%的患者反應於紫杉烷。因此，迫切需要能夠用於治療不再適合免疫療法的抗性癌症（像黑色素瘤）的其他方法。The current standard of care for melanoma is based on first-line immunotherapy, such as the use of immune checkpoint inhibitors such as nivolumab or pembrolizumab. Patients with an actionable mutation, such as those with a BRAF mutation, can receive targeted agents. Patients can receive several different lines of immunotherapy, but once it is no longer effective, standard chemotherapy (like dual carboplatin and paclitaxel or single-agent paclitaxel) can be used to continue treatment. However, response to chemotherapy is generally poor, with about 20% of patients responding to dual chemotherapy and only about 5% responding to taxanes. Therefore, additional approaches that can be used to treat resistant cancers that are no longer amenable to immunotherapy, like melanoma, are urgently needed.

令人驚奇地，已經發現，ATR抑制劑，例如AZD6738在之前已經接受用免疫療法治療的癌症患者（包括黑色素瘤患者）中特別有效，其中高比例的此類個體反應於後續ATR抑制。因此，已經接受先前的免疫療法的患者已經被鑒定為用ATR抑制劑（例如AZD6738）進行治療的靶群體。而且，ATR抑制似乎還增加對免疫療法具有抗性的癌症對用紫杉烷（例如紫杉醇）的化學療法的反應率。Surprisingly, it has been found that ATR inhibitors, such as AZD6738, are particularly effective in cancer patients, including melanoma patients, who have been previously treated with immunotherapy, with a high proportion of such individuals responding to subsequent ATR inhibition. Therefore, patients who have received prior immunotherapy have been identified as a target population for treatment with ATR inhibitors such as AZD6738. Moreover, ATR inhibition also appears to increase the response rate of immunotherapy-resistant cancers to chemotherapy with taxanes (eg, paclitaxel).

不希望受理論的約束，據信，用免疫療法治療的癌症可以變得對ATR抑制劑治療敏感，甚至在免疫療法本身在控制疾病方面停止發揮效力之後也是如此。Without wishing to be bound by theory, it is believed that cancers treated with immunotherapy can become sensitive to ATR inhibitor treatment even after immunotherapy itself ceases to be effective in controlling the disease.

本說明書之目的是提供ATR抑制劑（例如AZD6738）尤其是在治療癌症中之新用途。The purpose of this specification is to provide novel uses of ATR inhibitors such as AZD6738, especially in the treatment of cancer.

在本說明書之一個方面，提供了一種用於治療癌症的ATR抑制劑，其中該ATR抑制劑被投與至之前已經接受免疫療法的患者。In one aspect of the present specification, there is provided an ATR inhibitor for use in the treatment of cancer, wherein the ATR inhibitor is administered to a patient who has previously received immunotherapy.

在本說明書之另一方面，提供了一種治療需要此種治療的人類或動物患者的癌症之方法，該方法包括將ATR抑制劑投與至之前已經接受免疫療法的患者。In another aspect of the specification, there is provided a method of treating cancer in a human or animal patient in need of such treatment, the method comprising administering an ATR inhibitor to a patient who has previously received immunotherapy.

在本說明書之另外的方面，提供了ATR抑制劑在製造用於治療癌症的藥物中之用途，其中該藥物被投與至之前已經接受免疫療法的患者。In a further aspect of the present specification, there is provided the use of an ATR inhibitor in the manufacture of a medicament for the treatment of cancer, wherein the medicament is administered to a patient who has previously received immunotherapy.

在本說明書之另外的方面，提供了一種用於治療癌症的藥物組成物，其包含ATR抑制劑和藥學上可接受的賦形劑，其中該藥物組成物被投與至之前已經接受免疫療法的患者。In a further aspect of the present specification, there is provided a pharmaceutical composition for the treatment of cancer, comprising an ATR inhibitor and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is administered to a patient who has previously received immunotherapy patient.

在本說明書之另外的方面，提供了一種套組，該套組包含含有ATR抑制劑和至少一種藥學上可接受的賦形劑的藥物組成物以及該藥物組成物在治療癌症中的使用說明書，其中該ATR抑制劑被投與至之前已經接受免疫療法的患者。In a further aspect of the present specification, there is provided a kit comprising a pharmaceutical composition comprising an ATR inhibitor and at least one pharmaceutically acceptable excipient and instructions for use of the pharmaceutical composition in the treatment of cancer, wherein the ATR inhibitor is administered to a patient who has previously received immunotherapy.

本說明書中詳述的本發明不應被解釋為限於所述實施方式或實例中之任何一個。對於熟悉該項技術者來說，其他實施方式將是顯而易見的。The invention detailed in this specification should not be construed as limited to any one of the embodiments or examples described. Other embodiments will be apparent to those skilled in the art.

「一個/種（a/an）」係指「至少一個（種）」。在使用「一個/種（a/an）」表示給定要素的任何實施方式中，「一個/種（a/an）」可以表示一個（種）。在使用「一個/種（a/an）」表示給定要素的任何實施方式中，「一個/種（a/an）」可以表示1、2、3、4、5、6、7、8、9或10個（種）。"A/an" means "at least one (species)". In any implementation that uses "a/an" to refer to a given element, "a/an" may refer to one (a). In any embodiment where "a/an" is used to refer to a given element, "a/an" can refer to 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 (species).

當一個實施方式包括「一個/種（a/an）」元素X，隨後提及「該」元素X不意味著僅存在一個（種）該元素。代替地，以上「一個/種（a/an）」的解釋繼續適用以便「該」也意味著「至少一個（種）」。換句話說，包含「一個或一種元素X，其中該元素係……」的實施方式應該被解釋為「至少一個（種）元素X，其中該至少一個（種）元素X係……」。When an embodiment includes "a/an" element X, subsequent reference to "the" element X does not imply that there is only one (a) of that element. Instead, the above interpretation of "a/an" continues to apply so that "the" also means "at least one (a)". In other words, an embodiment containing "one or an element X, where the element is ..." should be interpreted as "at least one (kind) element X, where the at least one (kind) element X is ...".

「包含」意指給定的材料或元素可含有其他材料或元素。在任何實施方式中，在提及「包含」時，給定材料或元素可由該材料或元素（或材料或元素的組合）的至少10% w/w、至少20% w/w、至少30% w/w或至少40% w/w組成。在任何實施方式中，在提及「包含」時，「包含」還可以意指「由給定材料或元素組成」（「consisting of」或「consists of」）或「基本上由給定材料或元素組成」（「consisting essentially of」或「consists essentially of」）。"Comprising" means that a given material or element may contain other materials or elements. In any embodiment, where reference is made to "comprising", a given material or element may consist of at least 10% w/w, at least 20% w/w, at least 30% w/w of that material or element (or combination of materials or elements) w/w or at least 40% w/w composition. In any embodiment, when referring to "comprising", "comprising" can also mean "consisting of" ("consisting of" or "consists of") or "consisting essentially of the given material or Elemental composition" ("consisting essentially of" or "consists essentially of").

「由……組成」意指給定的材料或元素完全由該材料或元素（或材料或元素的組合）組成。在任何實施方式中，在提及「由……組成」時，給定材料或元素可以由該材料或元素的100% w/w組成。"Consisting of" means that a given material or element consists entirely of that material or element (or a combination of materials or elements). In any embodiment, when referring to "consisting of," a given material or element may consist of 100% w/w of that material or element.

「基本上由……組成」意指給定的材料或元素幾乎完全由該材料或元素（或材料或元素的組合）組成。在任何實施方式中，在提及「基本上由……組成」時，給定材料或元素可以由該材料或元素的至少50% w/w、至少60% w/w、至少70% w/w、至少80% w/w、至少90% w/w、至少95% w/w或至少99% w/w組成。"Consisting essentially of" means that a given material or element consists almost entirely of that material or element (or a combination of materials or elements). In any embodiment, where reference is made to "consisting essentially of," a given material or element may consist of at least 50% w/w, at least 60% w/w, at least 70% w/w of the material or element w, at least 80% w/w, at least 90% w/w, at least 95% w/w or at least 99% w/w.

在任何實施方式中，在用「係」或「可為」來定義材料或元素時，「係」或「可為」可以意指該材料或元素「由該材料或元素組成」或「基本上由該材料或元素組成」。In any embodiment, where "is" or "may" are used to define a material or element, "is" or "may" may mean that the material or element "consists of" or "substantially" consists of that material or element".

當提到「在一些實施方式中……」時，可以存在某個元素，該元素可以存在於說明書的任何部分中的合適實施方式中，而不僅僅是說明書的相同部分或文本區域中的合適實施方式中。When referring to "in some implementations..." there may be an element that is present in the appropriate implementation in any part of the specification, not just in the same part of the specification or where appropriate in the text area in the implementation.

當一個特徵「選自」具體的清單，則該特徵可以選自由具體的替代選擇組成的清單（即那些替代選擇並且不包含其他的清單）。When a feature is "selected" from a specific list, the feature may be selected from a list of specific alternatives (ie, those alternatives and no other list).

請求項係實施方式。治療用途 The claim item is the implementation. therapeutic use

在一個實施方式中，提供了一種用於治療癌症之ATR抑制劑，其中該ATR抑制劑被投與至之前已經接受免疫療法的患者。In one embodiment, there is provided an ATR inhibitor for use in the treatment of cancer, wherein the ATR inhibitor is administered to a patient who has previously received immunotherapy.

在一個實施方式中，提供了一種治療需要此種治療的人類或動物患者的癌症之方法，該方法包括將ATR抑制劑投與至之前已經接受免疫療法的患者。In one embodiment, there is provided a method of treating cancer in a human or animal patient in need of such treatment, the method comprising administering an ATR inhibitor to a patient who has previously received immunotherapy.

在一個實施方式中，提供了ATR抑制劑在製造用於治療癌症的藥物中之用途，其中該藥物被投與至之前已經接受免疫療法的患者。In one embodiment, there is provided the use of an ATR inhibitor in the manufacture of a medicament for the treatment of cancer, wherein the medicament is administered to a patient who has previously received immunotherapy.

在一個實施方式中，提供了一種用於治療癌症的藥物組成物，其包含ATR抑制劑和藥學上可接受的賦形劑，其中該藥物組成物被投與至之前已經接受免疫療法的患者。免疫療法 In one embodiment, there is provided a pharmaceutical composition for the treatment of cancer comprising an ATR inhibitor and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is administered to a patient who has previously received immunotherapy. Immunotherapy

如果患者「之前已經接受免疫療法」，這包括已經成功或未成功用免疫療法治療、使得他們的癌症分別反應於或未反應於治療的患者。之前已經接受免疫療法的患者可以由於治療失敗已經停止先前的治療，其中免疫療法對癌症的生長或疾病的健康影響不是或不再係積極控制的。在這樣的治療失敗時，癌症可以被描述為對免疫療法具有抗性。當癌症的一些固有的特徵阻止免疫療法起作用時，發生原發性抗性，然而，當在免疫療法治療過程中癌症變得具有抗性時，發生獲得性抗性，也稱為繼發性抗性。一些患者可以接受免疫療法作為輔助療法。對輔助的免疫療法復發的患者也可能被認為對免疫療法具有原發性抗性。If a patient has "previously received immunotherapy," this includes patients who have been successfully or unsuccessfully treated with immunotherapy, making their cancer respond or fail to respond, respectively. A patient who has previously received immunotherapy may have discontinued previous treatment due to treatment failure, where the immunotherapy's health effects on the growth of the cancer or the disease are not or are no longer actively controlled. When such treatments fail, the cancer can be described as resistant to immunotherapy. Primary resistance occurs when some inherent characteristic of the cancer prevents immunotherapy from working, however, acquired resistance, also known as secondary, occurs when the cancer becomes resistant during immunotherapy treatment resistance. Some patients can receive immunotherapy as adjunctive therapy. Patients who relapse to adjuvant immunotherapy may also be considered primary resistant to immunotherapy.

在一些實施方式中，患者的癌症對免疫療法可能具有抗性。In some embodiments, the patient's cancer may be resistant to immunotherapy.

在一些實施方式中，患者對免疫療法具有原發性抗性。在一個實施方式中，原發性抗性根據癌症免疫療法學會（SITC）建議被定義為具有 ≥ 6週的免疫療法藥物暴露和在進展之前小於6個月的進行性疾病或穩定疾病的最佳反應。In some embodiments, the patient is primary resistant to immunotherapy. In one embodiment, primary resistance is defined according to Society for Cancer Immunotherapy (SITC) recommendations as having ≥ 6 weeks of immunotherapy drug exposure and less than 6 months of progressive disease or stable disease prior to progression reaction.

在一些實施方式中，患者對免疫療法具有獲得性抗性。在一些實施方式中，獲得性抗性根據SITC建議被定義為具有 ≥ 6週的免疫療法藥物暴露和在進展之前超過6個月的完全反應、進行性疾病或穩定疾病的最佳反應。In some embodiments, the patient has acquired resistance to immunotherapy. In some embodiments, acquired resistance is defined according to SITC recommendations as having ≥ 6 weeks of immunotherapy drug exposure and a complete response, progressive disease, or best response with stable disease more than 6 months prior to progression.

「免疫療法」係利用患者自己的免疫系統治療疾病，例如癌症。其包括刺激患者的免疫系統的天然防禦，所以更好的是發現和攻擊身體內的有害物質（例如癌細胞），以及投與像免疫系統成分一樣起作用的藥物以便恢復或改善免疫系統工作方式以保護身體（例如發現和攻擊癌細胞）。"Immunotherapy" uses a patient's own immune system to treat diseases, such as cancer. It includes stimulating the patient's immune system's natural defenses, so better to find and attack harmful substances in the body (such as cancer cells), and administering drugs that act like components of the immune system to restore or improve the way the immune system works To protect the body (eg find and attack cancer cells).

在一些實施方式中，免疫療法可以包括用免疫檢查點抑制劑治療、嵌合抗原受體T-細胞療法、用細胞介素治療、用免疫調節劑治療、用癌症疫苗治療、用單株抗體治療、和/或用溶瘤病毒治療。In some embodiments, immunotherapy can include treatment with immune checkpoint inhibitors, chimeric antigen receptor T-cell therapy, treatment with interferons, treatment with immunomodulatory agents, treatment with cancer vaccines, treatment with monoclonal antibodies , and/or treatment with an oncolytic virus.

「檢查點抑制劑」包括任何阻斷免疫檢查點的物質：免疫系統的關鍵調控劑，當受到刺激時，其能抑制對免疫刺激的免疫反應。一些癌症能藉由刺激免疫檢查點靶來保護它們自身不受攻擊，所以，使用能阻止抑制檢查點的檢查點療法，從而恢復免疫系統功能。A "checkpoint inhibitor" includes any substance that blocks immune checkpoints: key regulators of the immune system that, when stimulated, suppress the immune response to immune stimulation. Some cancers protect themselves from attack by stimulating immune checkpoint targets, so using checkpoint therapy that blocks inhibition of checkpoints can restore immune system function.

示例性檢查點抑制劑包括PD-1抑制劑（例如派姆單抗[Keytruda®]、納武單抗[Opdivo®]、西米普利單抗（cemiplimab）[Libtayo®]、斯巴達珠單抗（spartalizumab）[PDR001]、卡瑞利珠單抗（camrelizumab）[SHR1210]、信迪利單抗（sintilimab）[IBI308]、替雷利珠單抗（tislelizumab）[BGB-A317]、特瑞普利單抗（toripalimab）[JS 001]、AMP-224或AMP-514、PD-L1抑制劑（例如阿特珠單抗（atezolizumab）[Tecentriq®]、阿維魯單抗（avelumab）[Bavencio®]、德瓦魯單抗（durvalumab）[Imfinzi®]、KN035、CK-301、AUNP12、CA-170或BMS-986189和CTLA-4抑制劑（例如伊匹單抗（ipilimumab）[Yervoy®]或曲美木單抗（tremelimumab））。Exemplary checkpoint inhibitors include PD-1 inhibitors (eg, pembrolizumab [Keytruda®], nivolumab [Opdivo®], cemiplimab [Libtayo®], spartazhul spartalizumab [PDR001], camrelizumab [SHR1210], sintilimab [IBI308], tislelizumab [BGB-A317], Ripilimab (toripalimab) [JS 001], AMP-224 or AMP-514, PD-L1 inhibitors (eg, atezolizumab [Tecentriq®], avelumab [ Bavencio®], durvalumab [Imfinzi®], KN035, CK-301, AUNP12, CA-170 or BMS-986189 and CTLA-4 inhibitors such as ipilimumab [Yervoy®] ] or tremelimumab).

在一些實施方式中，免疫療法可以包括用免疫檢查點抑制劑治療。In some embodiments, immunotherapy can include treatment with an immune checkpoint inhibitor.

在一些實施方式中，免疫療法可以包括用選自PD-1抑制劑、PD-L1抑制劑和CTLA-4抑制劑的免疫檢查點抑制劑治療。In some embodiments, immunotherapy can include treatment with an immune checkpoint inhibitor selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors.

在一些實施方式中，免疫療法可以包括用係PD-1抑制劑的免疫檢查點抑制劑治療。In some embodiments, immunotherapy can include treatment with an immune checkpoint inhibitor that is a PD-1 inhibitor.

在一些實施方式中，免疫療法可以包括用係PD-L1抑制劑的免疫檢查點抑制劑治療。In some embodiments, immunotherapy can include treatment with an immune checkpoint inhibitor that is a PD-L1 inhibitor.

在一些實施方式中，免疫療法可以包括用係CTLA-4抑制劑的免疫檢查點抑制劑治療。In some embodiments, immunotherapy can include treatment with an immune checkpoint inhibitor that is a CTLA-4 inhibitor.

在一些實施方式中，免疫療法可以包括用選自以下的免疫檢查點抑制劑治療：派姆單抗（pembrolizumab）、納武單抗（nivolumab）、西米普利單抗（cemiplimab）、斯巴達珠單抗（spartalizumab）、卡瑞利珠單抗（camrelizumab）、信迪利單抗（sintilimab）、替雷利珠單抗（tislelizumab）、特瑞普利單抗（toripalimab）、AMP-224、AMP-514、阿特珠單抗（atezolizumab）、阿維魯單抗（avelumab）、德瓦魯單抗（durvalumab）、KN035、CK-301、AUNP12、CA-170、BMS-986189、伊匹單抗（ipilimumab）或曲美木單抗（tremelimumab）。In some embodiments, immunotherapy can include treatment with an immune checkpoint inhibitor selected from the group consisting of: pembrolizumab, nivolumab, cemiplimab, spar spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224 , AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, Ipil monoclonal antibody (ipilimumab) or tremelimumab.

在一些實施方式中，免疫療法可以包括用選自以下的免疫檢查點抑制劑治療：派姆單抗、納武單抗、西米普利單抗、阿特珠單抗、阿維魯單抗、德瓦魯單抗和伊匹單抗。In some embodiments, the immunotherapy can include treatment with an immune checkpoint inhibitor selected from the group consisting of: pembrolizumab, nivolumab, cimipritimab, atezolizumab, avelumab , durvalumab, and ipilimumab.

在一些實施方式中，免疫療法可以包括用選自派姆單抗和納武單抗的免疫檢查點抑制劑治療。In some embodiments, immunotherapy can include treatment with an immune checkpoint inhibitor selected from the group consisting of pembrolizumab and nivolumab.

在一些實施方式中，免疫療法可以包括嵌合抗原受體T-細胞療法。In some embodiments, immunotherapy can include chimeric antigen receptor T-cell therapy.

「嵌合抗原受體（CAR）T-細胞療法」從患者的血液提取一些T-細胞、將它們與使得T-細胞學會如何附著到腫瘤細胞上的特殊的病毒混合，然後將細胞返回患者，以便它們能發現、附著並殺死癌。"Chimeric Antigen Receptor (CAR) T-Cell Therapy" takes some T-cells from a patient's blood, mixes them with a special virus that allows the T-cells to learn how to attach to tumor cells, and returns the cells to the patient, so that they can find, attach and kill cancer.

在一些實施方式中，免疫療法可以包括用細胞介素治療。In some embodiments, immunotherapy can include treatment with interferons.

「細胞介素」係在細胞之間攜帶資訊並刺激免疫細胞攻擊癌症的小的蛋白質。"Interferons" are small proteins that carry messages between cells and stimulate immune cells to attack cancer.

在一些實施方式中，免疫療法可以包括用免疫調節劑治療。In some embodiments, immunotherapy can include treatment with an immunomodulatory agent.

「免疫調節劑」係通常促進部分免疫系統以治療某些類型的癌症的藥物。"Immune modulators" are drugs that usually boost parts of the immune system to treat certain types of cancer.

在一些實施方式中，免疫療法可以包括用癌症疫苗治療。In some embodiments, immunotherapy can include treatment with a cancer vaccine.

「癌症疫苗」係被放入體內以激活對癌症的免疫反應的物質。它們可以被預防性地使用或者增強身體的免疫反應，實現更有效的治療。"Cancer vaccines" are substances that are put into the body to activate the immune response to cancer. They can be used prophylactically or to boost the body's immune response for more effective treatment.

在一些實施方式中，免疫療法可以包括用單株抗體治療。In some embodiments, immunotherapy can include treatment with monoclonal antibodies.

「單株抗體」（mAb或MoAb）係人造版的免疫系統蛋白。可以設計單株抗體以攻擊非常特定部分的癌細胞。"Monoclonal antibodies" (mAbs or MoAbs) are man-made versions of immune system proteins. Monoclonal antibodies can be designed to attack very specific portions of cancer cells.

在一些實施方式中，免疫療法可以包括用溶瘤病毒治療。In some embodiments, immunotherapy can include treatment with an oncolytic virus.

「溶瘤病毒」治療使用已經在實驗室被修飾以感染並殺死某些腫瘤細胞的病毒。"Oncolytic virus" treatments use viruses that have been modified in the lab to infect and kill certain tumor cells.

在一些實施方式中，免疫療法可以包括用一種免疫療法劑治療。In some embodiments, immunotherapy can include treatment with an immunotherapy agent.

在一些實施方式中，免疫療法可以包括用超過一種免疫療法劑治療，例如PD-L1或PD-1抗體與CTLA-4抗體組合。ATR 抑制 In some embodiments, immunotherapy can include treatment with more than one immunotherapy agent, eg, PD-L1 or PD-1 antibody in combination with CTLA-4 antibody. ATR inhibition

「ATR抑制劑」係在體外或在體內減弱ATR酶的活性的任何化合物。ATR抑制劑可以是選擇性的或非選擇性的、小分子或生物分子。An "ATR inhibitor" is any compound that attenuates the activity of an ATR enzyme in vitro or in vivo. ATR inhibitors can be selective or non-selective, small molecules or biomolecules.

示例性ATR抑制劑包括AZD6738、M6620、BAY-1895344、EPT-46464、VE-821和VX-970。Exemplary ATR inhibitors include AZD6738, M6620, BAY-1895344, EPT-46464, VE-821 and VX-970.

在一些實施方式中，ATR抑制劑可以選自AZD6738、M6620、BAY-1895344、EPT-46464、VE-821和VX-970。In some embodiments, the ATR inhibitor can be selected from AZD6738, M6620, BAY-1895344, EPT-46464, VE-821 and VX-970.

在一些實施方式中，ATR抑制劑可以是AZD6738。In some embodiments, the ATR inhibitor can be AZD6738.

在一些實施方式中，AZD6738可以是化合物 (I) 或其藥學上可接受的鹽。In some embodiments, AZD6738 can be Compound (I) or a pharmaceutically acceptable salt thereof.

術語「藥學上可接受的」通常是指對象（例如鹽、劑型或賦形劑）係適合在患者中使用的和/或具有臨床或商業優勢。藥學上可接受的鹽的實例清單可以發現於：Handbook of Pharmaceutical Salts: Properties, Selection and Use [藥用鹽手冊：特性、選擇和使用], P. H. Stahl和C.G. Wermuth, 編輯，Weinheim/Zurich: Wiley-VCH/VFiCA, 2002版或後續版本。The term "pharmaceutically acceptable" generally means that a subject (eg, a salt, dosage form, or excipient) is suitable for use in a patient and/or has a clinical or commercial advantage. A list of examples of pharmaceutically acceptable salts can be found in: Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C.G. Wermuth, editors, Weinheim/Zurich: Wiley- VCH/VFiCA, version 2002 or later.

在一些實施方式中，AZD6738可以是呈無鹽形式的化合物 (I)（例如中性或兩性離子形式，或例如游離鹼或游離酸形式）。In some embodiments, AZD6738 can be Compound (I) in an unsalted form (e.g., neutral or zwitterionic form, or, e.g., free base or free acid form).

在一些實施方式中，AZD6738可以是化合物 (I) 的藥學上可接受的鹽。In some embodiments, AZD6738 can be a pharmaceutically acceptable salt of Compound (I).

化合物 (I) 的適合的藥學上可接受的鹽係例如酸加成鹽。化合物 (I) 的酸加成鹽可以藉由使該化合物與適合的無機酸或有機酸在技術人員已知的條件下接觸來形成。Suitable pharmaceutically acceptable salts of compound (I) are, for example, acid addition salts. Acid addition salts of compound (I) can be formed by contacting the compound with a suitable inorganic or organic acid under conditions known to the skilled person.

酸加成鹽例如可以使用選自鹽酸、氫溴酸、硫酸和磷酸的無機酸來形成。酸加成鹽也可以使用選自檸檬酸、富馬酸、馬來酸和甲磺酸的有機酸來形成。Acid addition salts can be formed, for example, using inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. Acid addition salts can also be formed using organic acids selected from the group consisting of citric acid, fumaric acid, maleic acid and methanesulfonic acid.

化合物 (I) 的另一種適合的藥學上可接受的鹽係例如在向人體或動物體投與化合物 (I) 之後所述人體或動物體內所形成的鹽。Another suitable pharmaceutically acceptable salt of Compound (I) is, for example, a salt formed in a human or animal body following administration of Compound (I) to said human or animal body.

在一些實施方式中，ATR抑制劑可以是AZD6738，其在為期28天的週期的第1至21天投與。In some embodiments, the ATR inhibitor can be AZD6738, which is administered on days 1 to 21 of a 28-day cycle.

「為期28天的週期」係單個治療期，其可以對給定的患者連續重複，或可以在分散的週期之間帶治療間隙地（例如1天、2天、3天、4天、5天、6天、7天、8天、9天、10天、11天、12天、13天、14天、30天或60天的治療間隙）進行重複。A "28-day cycle" is a single treatment period, which may be repeated continuously for a given patient, or may be interspersed with treatment breaks between discrete cycles (eg, 1 day, 2 days, 3 days, 4 days, 5 days , 6, 7, 8, 9, 10, 11, 12, 13, 14, 30, or 60-day treatment intervals).

在一些實施方式中，ATR抑制劑可以是AZD6738，其在為期28天的週期的第1至14天投與。In some embodiments, the ATR inhibitor can be AZD6738, which is administered on days 1 to 14 of a 28-day cycle.

在一些實施方式中，ATR抑制劑可以是AZD6738，其在為期28天的週期的第1至7天投與。In some embodiments, the ATR inhibitor can be AZD6738, which is administered on days 1 to 7 of a 28-day cycle.

在一些實施方式中，ATR抑制劑可以是AZD6738，其在為期28天的週期內根據兩週進行/兩週停止（14天進行/14天停止）的時間表投與。In some embodiments, the ATR inhibitor can be AZD6738, which is administered on a two-week on/two-week-off (14-day on/14-day off) schedule over a 28-day cycle.

在一些實施方式中，ATR抑制劑可以是AZD6738，其在為期28天的週期內連續7天投與。In some embodiments, the ATR inhibitor can be AZD6738, which is administered for 7 consecutive days in a 28-day cycle.

在一些實施方式中，ATR抑制劑可以是AZD6738，其在為期28天的週期內連續14天投與。In some embodiments, the ATR inhibitor can be AZD6738, which is administered for 14 consecutive days in a 28-day cycle.

在一些實施方式中，ATR抑制劑可以是AZD6738，其以30 mg至500 mg之間的總日劑量被投與。In some embodiments, the ATR inhibitor can be AZD6738, which is administered in a total daily dose of between 30 mg and 500 mg.

在一些實施方式中，ATR抑制劑可以是AZD6738，其以40 mg、60 mg、80 mg、160 mg、240 mg、320 mg或480 mg的總日劑量被投與。In some embodiments, the ATR inhibitor can be AZD6738, which is administered in a total daily dose of 40 mg, 60 mg, 80 mg, 160 mg, 240 mg, 320 mg, or 480 mg.

在一些實施方式中，ATR抑制劑可以是AZD6738，其以480 mg的總日劑量被投與。In some embodiments, the ATR inhibitor can be AZD6738, which is administered in a total daily dose of 480 mg.

在一些實施方式中，ATR抑制劑可以是AZD6738，其以240 mg劑量每日兩次（即以480 mg的總日劑量，以兩次分開的份額被投與，每份額由50%的總日劑量組成）被投與。In some embodiments, the ATR inhibitor can be AZD6738, which is administered at a dose of 240 mg twice daily (ie, at a total daily dose of 480 mg, in two divided portions, each portion consisting of 50% of the total daily dose) dose composition) is administered.

在一些實施方式中，ATR抑制劑可以是AZD6738，其在為期28天的週期的第1至21天以240 mg劑量每天兩次被投與。In some embodiments, the ATR inhibitor can be AZD6738, which is administered at a dose of 240 mg twice daily on days 1 to 21 of a 28-day cycle.

在一些實施方式中，ATR抑制劑可以是AZD6738，其在為期28天的週期內連續7天以240 mg劑量每天兩次被投與。In some embodiments, the ATR inhibitor may be AZD6738, which is administered at a dose of 240 mg twice daily for 7 consecutive days in a 28-day cycle.

在一些實施方式中，ATR抑制劑可以是AZD6738，其在為期28天的週期的第1至7天以240 mg劑量每天兩次被投與。In some embodiments, the ATR inhibitor can be AZD6738, which is administered at a dose of 240 mg twice daily on days 1 to 7 of a 28-day cycle.

在一些實施方式中，ATR抑制劑可以是AZD6738，其在為期28天的週期內根據兩週進行/兩週停止的時間表每天兩次被投與。In some embodiments, the ATR inhibitor can be AZD6738, which is administered twice daily over a 28-day cycle according to a two-week on/two-week off schedule.

在一些實施方式中，ATR抑制劑可以是AZD6738，其在為期28天的週期內連續14天以240 mg劑量每天兩次被投與。In some embodiments, the ATR inhibitor can be AZD6738, which is administered at a dose of 240 mg twice daily for 14 consecutive days in a 28 day cycle.

在一些實施方式中，ATR抑制劑可以是AZD6738，其在為期28天的週期的第1至14天以240 mg劑量每天兩次被投與。癌症 In some embodiments, the ATR inhibitor may be AZD6738, which is administered at a dose of 240 mg twice daily on days 1 to 14 of a 28-day cycle. cancer

在本說明書中，「癌症」與腫瘤和病變同義使用。癌症可能包括原發癌以及繼發癌和轉移癌。腫瘤可以是可檢測的或不可檢測的，例如微轉移。In this specification, "cancer" is used synonymously with tumors and lesions. Cancers may include primary cancers as well as secondary and metastatic cancers. Tumors can be detectable or undetectable, such as micrometastases.

「癌症的治療」、「治療癌症」和類似術語包括治療現有癌症和/或預防癌症。在一些實施方式中，治療可在一個或多個症狀已經出現之後進行。在其他實施方式中，可以在沒有症狀的情況下進行治療。例如，可在症狀發作之前（例如，由於疾病史和/或考慮到遺傳或其他易感因素）開始對易感個體進行治療。症狀消退後也可繼續治療，例如以防止或延遲它們復發。"Treatment of cancer," "treatment of cancer," and similar terms include treatment of existing cancer and/or prevention of cancer. In some embodiments, treatment may occur after one or more symptoms have occurred. In other embodiments, treatment can be performed in the absence of symptoms. For example, treatment of susceptible individuals may be initiated prior to the onset of symptoms (eg, due to disease history and/or due to genetic or other predisposing factors). Treatment may also be continued after symptoms subside, for example, to prevent or delay their recurrence.

在一些實施方式中，癌症的治療或治療癌症可以意味著治療和預防癌症。In some embodiments, treatment of cancer or treating cancer can mean treating and preventing cancer.

在一些實施方式中，癌症的治療或治療癌症可以意味著治療癌症。In some embodiments, treatment of cancer or treating cancer can mean treating cancer.

在一些實施方式中，癌症的治療或治療癌症可以意味著預防癌症。In some embodiments, treatment of cancer or treating cancer can mean preventing cancer.

在一些實施方式中，癌症可以選自黑色素瘤、胃癌、肉瘤、大腸癌、神經內分泌癌、肝細胞癌、非小細胞肺癌、以及鱗狀頭頸癌。In some embodiments, the cancer may be selected from the group consisting of melanoma, gastric cancer, sarcoma, colorectal cancer, neuroendocrine cancer, hepatocellular carcinoma, non-small cell lung cancer, and squamous head and neck cancer.

在一些實施方式中，癌症可以選自黑色素瘤、胃癌、肉瘤、大腸癌、神經內分泌癌和肝細胞癌。In some embodiments, the cancer may be selected from the group consisting of melanoma, gastric cancer, sarcoma, colorectal cancer, neuroendocrine cancer, and hepatocellular carcinoma.

在一些實施方式中，癌症可以選自黑色素瘤、胃癌、非小細胞肺癌、以及鱗狀頭頸癌。In some embodiments, the cancer can be selected from melanoma, gastric cancer, non-small cell lung cancer, and squamous head and neck cancer.

在一些實施方式中，癌症可以選自黑色素瘤和胃癌。In some embodiments, the cancer can be selected from melanoma and gastric cancer.

在一些實施方式中，癌症可以是黑色素瘤。已知黏膜黑色素瘤和肢端黑色素瘤係特別難以治療的黑色素瘤的組織學亞型。然而，在用本文所述之治療方法治療的患者中觀察到該等亞型的反應。In some embodiments, the cancer can be melanoma. Mucosal melanoma and acral melanoma are known histological subtypes of melanoma that are particularly difficult to treat. However, responses of these subtypes have been observed in patients treated with the treatment methods described herein.

在一些實施方式中，癌症可以是皮膚黑色素瘤。In some embodiments, the cancer can be cutaneous melanoma.

在一些實施方式中，癌症可以是肛門附近皮膚黑色素瘤。In some embodiments, the cancer may be melanoma of the skin near the anus.

在一些實施方式中，癌症可以是肢端黑色素瘤。In some embodiments, the cancer may be acral melanoma.

在一些實施方式中，癌症可以是黏膜黑色素瘤。In some embodiments, the cancer can be mucosal melanoma.

在一些實施方式中，癌症可以是早期的、活躍進行性的、晚期的（例如局部晚期的）、侵入性的、轉移性的、和/或耐藥性的癌症。In some embodiments, the cancer may be early, actively progressive, advanced (eg, locally advanced), invasive, metastatic, and/or drug-resistant cancer.

在一些實施方式中，癌症可以是局部晚期癌症。In some embodiments, the cancer may be locally advanced cancer.

在一些實施方式中，癌症可以是晚期的和/或轉移性癌症。In some embodiments, the cancer may be advanced and/or metastatic cancer.

在一些實施方式中，癌症可以是局部晚期和/或轉移性癌症。In some embodiments, the cancer may be locally advanced and/or metastatic cancer.

在一些實施方式中，癌症可以是轉移性癌症。In some embodiments, the cancer can be metastatic cancer.

在一些實施方式中，癌症可以是轉移性黑色素瘤。In some embodiments, the cancer can be metastatic melanoma.

在一些實施方式中，癌症可以是侵入性癌症。In some embodiments, the cancer can be an invasive cancer.

在一些實施方式中，癌症可以是IV期黑色素瘤。In some embodiments, the cancer can be stage IV melanoma.

在一些實施方式中，癌症可以是III期不可切除的黑色素瘤。患者選擇 In some embodiments, the cancer can be stage III unresectable melanoma. patient selection

在一些實施方式中，癌症可以是ATM缺陷型。In some embodiments, the cancer can be ATM deficient.

當癌症係「ATM缺陷型」時，癌細胞比相同類型的正常、非癌細胞表現更少的ATM蛋白。例如，當藉由IHC蛋白質染色分析時，癌細胞可能表現相同類型的正常細胞典型地表現的總ATM蛋白的 ≤ 5%、≤ 10%、≤ 20%、≤ 30%、≤ 40%、≤ 50%、≤ 60%、≤ 70%、≤ 80%、≤ 90%或 ＜ 100%。ATM缺陷型癌細胞可能還在它們的ATM基因中包含雙等位基因有害突變。When the cancer line is "ATM-deficient," the cancer cells express less ATM protein than normal, non-cancer cells of the same type. For example, when analyzed by IHC protein staining, cancer cells may exhibit ≤ 5%, ≤ 10%, ≤ 20%, ≤ 30%, ≤ 40%, ≤ 50% of the total ATM protein typically exhibited by normal cells of the same type %, ≤ 60%, ≤ 70%, ≤ 80%, ≤ 90%, or < 100%. ATM-deficient cancer cells may also contain biallelic deleterious mutations in their ATM gene.

在一些實施方式中，癌症可以是ARID1A缺陷型。In some embodiments, the cancer can be ARID1A deficient.

當癌症係「ARID1A缺陷型」時，癌細胞比相同類型的正常、非癌細胞表現更少的ARID1A蛋白。例如，當藉由IHC蛋白質染色分析時，癌細胞可能表現相同類型的正常細胞典型地表現的總ARID1A蛋白的 ≤ 5%、≤ 10%、≤ 20%、≤ 30%、≤ 40%、≤ 50%、≤ 60%、≤ 70%、≤ 80%、≤ 90%或 ＜ 100%。ARID1A缺陷型癌細胞可能還在ARID1A基因中包含突變（例如功能缺失突變，例如無義突變）。When the cancer line was "ARID1A-deficient," the cancer cells expressed less ARID1A protein than normal, non-cancer cells of the same type. For example, when analyzed by IHC protein staining, cancer cells may exhibit ≤ 5%, ≤ 10%, ≤ 20%, ≤ 30%, ≤ 40%, ≤ 50% of the total ARID1A protein typically exhibited by normal cells of the same type %, ≤ 60%, ≤ 70%, ≤ 80%, ≤ 90%, or < 100%. ARID1A-deficient cancer cells may also contain mutations (eg, loss-of-function mutations, such as nonsense mutations) in the ARID1A gene.

在一些實施方式中，癌症可以是ATM缺陷型黑色素瘤。In some embodiments, the cancer can be ATM-deficient melanoma.

在一些實施方式中，癌症可以是ARID1A缺陷型黑色素瘤。In some embodiments, the cancer can be ARID1A-deficient melanoma.

在一些實施方式中，ATR抑制劑作為二線療法（即在患者免疫療法失敗後）被投與至患者。In some embodiments, the ATR inhibitor is administered to the patient as second-line therapy (ie, after the patient has failed immunotherapy).

在一些實施方式中，ATR抑制劑作為三線療法被投與至患者。接受ATR抑制劑（作為三線療法）的患者可能在用免疫療法治療之前已經接受BRAF和MEK抑制劑（例如達拉非尼和曲美替尼）治療。臨床性質 In some embodiments, the ATR inhibitor is administered to the patient as third line therapy. Patients receiving ATR inhibitors (as third-line therapy) may have been treated with BRAF and MEK inhibitors (eg, dabrafenib and trametinib) prior to treatment with immunotherapy. clinical nature

在一個實施方式中，提供了用於治療癌症的ATR抑制劑，其中該ATR抑制劑被投與至之前已經接受免疫療法的患者，並且ATR抑制劑進行治療取得10%-50%、10%-40%、10%-35%、20%-35%、25%-40%、30%-35%、大於10%、大於20%、大於30%、大於40%、大於50%、大於60%、或大於70%的客觀反應率。In one embodiment, there is provided an ATR inhibitor for the treatment of cancer, wherein the ATR inhibitor is administered to a patient who has previously received immunotherapy, and treatment with the ATR inhibitor achieves 10%-50%, 10%- 40%, 10%-35%, 20%-35%, 25%-40%, 30%-35%, more than 10%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60% , or an objective response rate greater than 70%.

「客觀反應率」係在基線處具有可測定的疾病並且取得至少1次反應的患者的百分率。"Objective response rate" is the percentage of patients with measurable disease at baseline who achieved at least 1 response.

「RECIST標準」（例如RECIST 1.1標準）陳述在以下網址：https://recist.eortc.org/並且描述於Eur. J. Cancer [歐洲癌症雜誌] 2016, 62, 第132-137頁。"RECIST criteria" (eg, RECIST 1.1 criteria) are stated at: https://recist.eortc.org/ and described in Eur. J. Cancer 2016, 62, pp. 132-137.

在一個實施方式中，提供了用於治療癌症的ATR抑制劑，其中該ATR抑制劑被投與至之前已經接受免疫療法的患者，並且用ATR抑制劑進行治療取得25%-100%、25%-90%、40%-80%或50%-70%的臨床受益率。In one embodiment, there is provided an ATR inhibitor for the treatment of cancer, wherein the ATR inhibitor is administered to a patient who has previously received immunotherapy, and treatment with the ATR inhibitor achieves 25%-100%, 25% -90%, 40%-80% or 50%-70% clinical benefit rate.

「臨床受益率」係客觀反應率加以下患者的百分率，該患者在第一次掃描時的最佳反應係穩定疾病，即他們在第一次掃描時沒有疾病進展（完全反應+部分反應+穩定疾病）。The "clinical benefit rate" is the objective response rate plus the percentage of patients whose best response at the first scan is stable disease, i.e. they have no disease progression at the first scan (complete response + partial response + stable disease disease).

在一個實施方式中，提供了用於治療癌症的ATR抑制劑，其中該ATR抑制劑被投與至之前已經接受免疫療法的患者，並且用ATR抑制劑進行治療取得大於6個月、大於7個月、大於8個月、較佳的是大於9個月的無進展生存期。在一個實施方式中，用ATR抑制劑進行治療取得3個月-24個月的無進展生存期。In one embodiment, there is provided an ATR inhibitor for the treatment of cancer, wherein the ATR inhibitor is administered to a patient who has previously received immunotherapy, and treatment with the ATR inhibitor achieves greater than 6 months, greater than 7 months, greater than 8 months, preferably greater than 9 months of progression-free survival. In one embodiment, treatment with an ATR inhibitor results in a progression free survival of 3 months to 24 months.

「無進展生存期」或「PFS」係在治療期間和之後患者度過的沒有疾病惡化的時長。PFS可以使用Kaplan-Meier法測定。"Progression-free survival" or "PFS" is the length of time a patient spends without disease progression during and after treatment. PFS can be determined using the Kaplan-Meier method.

在一個實施方式中，提供了用於治療癌症的ATR抑制劑，其中該ATR抑制劑被投與至之前已經接受免疫療法的患者，並且用ATR抑制劑進行治療取得至少2個月、至少3個月、至少4個月、較佳的是至少5個月的反應持續期。在一個實施方式中，用ATR抑制劑進行治療取得2個月-6個月的反應持續期。In one embodiment, there is provided an ATR inhibitor for the treatment of cancer, wherein the ATR inhibitor is administered to a patient who has previously received immunotherapy, and treatment with the ATR inhibitor is achieved for at least 2 months, at least 3 months A duration of response of at least 4 months, preferably at least 5 months. In one embodiment, treatment with an ATR inhibitor achieves a response duration of 2 months to 6 months.

「反應持續期」或「DoR」係腫瘤持續反應於治療且沒有癌症生長或擴散的時長。The "duration of response" or "DoR" is the length of time a tumor continues to respond to treatment without the cancer growing or spreading.

「總體存活期」或「OS」係從治療開始直到患者仍活著的時長。"Overall survival" or "OS" is the length of time from the start of treatment until the patient is still alive.

在一個實施方式中，提供了用於治療癌症的ATR抑制劑，其中該ATR抑制劑被投與至之前已經接受免疫療法的患者，並且用ATR抑制劑進行治療不會在癌症患者中造成任何嚴重的副作用。In one embodiment, there is provided an ATR inhibitor for the treatment of cancer, wherein the ATR inhibitor is administered to a patient who has previously received immunotherapy, and treatment with the ATR inhibitor does not cause any seriousness in the cancer patient side effects.

在一些實施方式中，嚴重副作用可定義為4級或5級不良事件。In some embodiments, serious side effects can be defined as grade 4 or 5 adverse events.

「4級或5級不良事件」可根據不良事件通用術語標準（CTCAE）進行分類。組合治療 "Grade 4 or 5 adverse events" can be classified according to the Common Terminology Criteria for Adverse Events (CTCAE). combination therapy

在一個實施方式中，提供了用於治療癌症的ATR抑制劑，其中該ATR抑制劑與紫杉烷組合被投與至之前已經接受免疫療法的患者。In one embodiment, there is provided an ATR inhibitor for the treatment of cancer, wherein the ATR inhibitor is administered in combination with a taxane to a patient who has previously received immunotherapy.

當使用術語「組合」時，應理解的是這係指同時、分開或順序投與。When the term "combination" is used, it should be understood that this refers to simultaneous, separate or sequential administration.

在一些實施方式中，可以同時、分開和/或順序投與組合。In some embodiments, the combinations may be administered simultaneously, separately, and/or sequentially.

在一些實施方式中，可以同時投與組合。In some embodiments, the combination can be administered simultaneously.

在一些實施方式中，可以分開投與組合。In some embodiments, the combination may be administered separately.

在一些實施方式中，可以順序投與組合。In some embodiments, the combination may be administered sequentially.

在順序的或分開的投與組合的情況下，延遲投與第二組分不應當導致該組合的有益作用喪失。In the case of a combination of sequential or separate administration, delayed administration of the second component should not result in a loss of the beneficial effect of the combination.

「紫杉烷」係具有紫衫烯核的二萜化合物。它們可以作為天然產物被分離或以合成方式或半合成方式來製備。"Taxane" is a diterpene compound having a taxene nucleus. They can be isolated as natural products or prepared synthetically or semi-synthetically.

在一些實施方式中，紫杉烷可以選自紫杉醇、多烯紫杉醇、紫衫酚（cremophor EL-紫杉醇）、abraxane（nab -紫杉醇）和卡巴他賽（cabazitaxel）。In some embodiments, the taxane may be selected from paclitaxel, docetaxel, taxol (cremophor EL-paclitaxel), abraxane ( nab -paclitaxel), and cabazitaxel.

在一些實施方式中，紫杉烷係紫杉醇。In some embodiments, the taxane is paclitaxel.

在一些實施方式中，紫杉烷可以是紫杉醇，其在為期28天的週期的第1天、第8天和第15天投與。In some embodiments, the taxane can be paclitaxel, which is administered on days 1, 8, and 15 of a 28-day cycle.

在一些實施方式中，紫杉烷可以是紫杉醇，其在為期28天的週期的第1天、第8天和第15天每日一次被投與。In some embodiments, the taxane may be paclitaxel, which is administered once daily on days 1, 8, and 15 of a 28-day cycle.

在一些實施方式中，紫杉烷可以是紫杉醇，其以80 mg/m² 的量被投與。In some embodiments, the taxane can be paclitaxel, which is administered in an amount of 80 mg/m ² .

在一些實施方式中，紫杉烷可以是紫杉醇，在為期28天的週期的第1天、第8天和第15天以80 mg/m² 的量被投與。In some embodiments, the taxane may be paclitaxel administered in an amount of 80 mg/m2 on days ¹ , 8, and 15 of a 28-day cycle.

在一些實施方式中，紫杉烷可以是紫杉醇，其在為期28天的週期的第1天、第8天和第15天以80 mg/m² 的量每日一次被投與。套組 In some embodiments, the taxane may be paclitaxel, which is administered once daily on days 1, 8, and 15 of a 28-day cycle in an amount of 80 mg/m ² . set

在一個實施方式中，提供了一種套組，該套組包含含有ATR抑制劑和至少一種藥學上可接受的賦形劑的藥物組成物以及該藥物組成物在治療癌症中的使用說明書，其中該ATR抑制劑被投與至之前已經接受免疫療法的患者。具體的實施方式 In one embodiment, a kit is provided, the kit comprising a pharmaceutical composition comprising an ATR inhibitor and at least one pharmaceutically acceptable excipient and instructions for use of the pharmaceutical composition in the treatment of cancer, wherein the ATR inhibitors are administered to patients who have previously received immunotherapy. specific implementation

在一個實施方式中，提供了用於治療癌症的ATR抑制劑，其中該ATR抑制劑係AZD6738，其與紫杉烷組合被投與至之前已經接受用免疫檢查點抑制劑的療法的患者。In one embodiment, there is provided an ATR inhibitor for the treatment of cancer, wherein the ATR inhibitor is AZD6738, which is administered in combination with a taxane to a patient who has previously received therapy with an immune checkpoint inhibitor.

在一個實施方式中，提供了用於治療癌症的ATR抑制劑，該癌症選自黑色素瘤、胃癌、肉瘤、大腸癌、神經內分泌癌、肝細胞癌、非小細胞肺癌、以及鱗狀頭頸癌，其中該ATR抑制劑係AZD6738，其與紫杉醇組合被投與至之前已經接受用免疫檢查點抑制劑的療法的患者，該免疫檢查點抑制劑選自派姆單抗、納武單抗、西米普利單抗、斯巴達珠單抗、卡瑞利珠單抗、信迪利單抗、替雷利珠單抗、特瑞普利單抗、AMP-224、AMP-514、阿特珠單抗、阿維魯單抗、德瓦魯單抗、KN035、CK-301、AUNP12、CA-170、BMS-986189、伊匹單抗或曲美木單抗。In one embodiment, there is provided an ATR inhibitor for use in the treatment of cancer selected from the group consisting of melanoma, gastric cancer, sarcoma, colorectal cancer, neuroendocrine cancer, hepatocellular carcinoma, non-small cell lung cancer, and squamous head and neck cancer, wherein the ATR inhibitor is AZD6738, which is administered in combination with paclitaxel to patients who have previously received therapy with an immune checkpoint inhibitor selected from the group consisting of pembrolizumab, nivolumab, sago Prilimumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalizumab, AMP-224, AMP-514, atezolizumab mAb, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab, or tremelimumab.

在一個實施方式中，提供了用於治療黑色素瘤的ATR抑制劑，其中該ATR抑制劑係AZD6738，其與紫杉醇組合被投與至之前已經接受用免疫檢查點抑制劑的療法的患者，該免疫檢查點抑制劑選自派姆單抗、納武單抗、西米普利單抗、斯巴達珠單抗、卡瑞利珠單抗、信迪利單抗、替雷利珠單抗、特瑞普利單抗、AMP-224、AMP-514、阿特珠單抗、阿維魯單抗、德瓦魯單抗、KN035、CK-301、AUNP12、CA-170、BMS-986189、伊匹單抗或曲美木單抗。In one embodiment, there is provided an ATR inhibitor for the treatment of melanoma, wherein the ATR inhibitor is AZD6738, which is administered in combination with paclitaxel to a patient who has previously received therapy with an immune checkpoint inhibitor, the immune The checkpoint inhibitor is selected from the group consisting of pembrolizumab, nivolumab, simipritizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, Toripalimab, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, pimumab or tremelimumab.

在一個實施方式中，提供了用於治療黑色素瘤的ATR抑制劑，其中該ATR抑制劑係AZD6738，其與紫杉醇組合被投與至之前已經接受用選自派姆單抗和納武單抗的免疫檢查點抑制劑的療法的患者。實例 縮寫 In one embodiment, there is provided an ATR inhibitor for use in the treatment of melanoma, wherein the ATR inhibitor is AZD6738, which is administered in combination with paclitaxel to an ATR inhibitor that has previously been treated with a drug selected from the group consisting of pembrolizumab and nivolumab. patients on immune checkpoint inhibitor therapy. instance abbreviation

AE-不良事件 AGC-晚期胃癌 ATM-共濟失調性毛細血管擴張突變的 ATR-共濟失調性毛細管擴張和Rad3-相關的蛋白 CRF-病例報告形式（電子版/紙質版） CSA-臨床研究協議 CSR-臨床研究報告 CTCAE-不良事件的公用術語標準 CtDNA-循環腫瘤DNA DAE-由於不良事件調查產品的停用 DNA-去氧核糖核酸 EC-倫理委員會，機構審查委員會（IRB）和獨立倫理委員會（IEC）的代名詞 ECG-心電圖 GCP-良好臨床實踐 ICH-國際協調大會 IP-調查產物 LSLV-最後的受試者最後訪視 OAE-其他重大不良事件 PI-主要研究者 SAE-嚴重不良事件臨床試驗方案 AE - Adverse Events AGC - Advanced Gastric Cancer ATM - Ataxia Telangiectasia Mutated ATR - Ataxia Telangiectasia and Rad3-Related Proteins CRF - Case Report Form (Electronic/Paper Version) CSA - Clinical Research Protocol CSR - Clinical Research Reports CTCAE - Common Terminology Criteria for Adverse Events CtDNA - Circulating Tumor DNA DAE - Investigation of Product Discontinuation Due to Adverse Events DNA - Deoxyribonucleic Acid EC - Ethics Committees, Institutional Review Boards (IRBs) and Independent Ethics Committees ( IEC) synonymous with ECG - Electrocardiogram GCP - Good Clinical Practice ICH - International Conference on Harmonization IP - Survey Product LSLV - Last Subject Last Visit OAE - Other Significant Adverse Events PI - Principal Investigator SAE - Serious Adverse Events Clinical Trials Protocol

介紹 ：為了確定AZD6738的效力和劑量，根據以下基本方案在標準化學療法已經失敗的轉移性癌症患者中進行AZD6738與紫杉醇組合的單中心開放標籤I期研究。 Introduction : To determine the potency and dose of AZD6738, a single-center open-label Phase I study of AZD6738 in combination with paclitaxel was conducted in patients with metastatic cancer who had failed standard chemotherapy according to the following basic protocol.

主要目標和結果量度Main Objectives and Outcome Measures 主要目標main target 結果量度Outcome measure 評估AZD6738與紫杉醇組合的安全性和耐受性。To evaluate the safety and tolerability of AZD6738 in combination with paclitaxel. •       AE/SAE •       生命體征。 •       臨床化學/血液學參數的收集。 •       ECG將針對每一份ECG記錄以下參數：ECG的日期和時間、心率（跳動次數/分鐘）、QT（ms）、QTcB（ms）、竇性節律（係/否）。 •       整體評估（正常/不正常）。• AE/SAE • vital signs. • Collection of clinical chemistry/hematology parameters. • ECG will record the following parameters for each ECG: date and time of ECG, heart rate (beats/min), QT (ms), QTcB (ms), sinus rhythm (yes/no). • Overall assessment (normal/abnormal). 確定在患有難治性癌症的病人中 AZD6738與固定劑量的紫杉醇組合給藥時的最大耐受劑量（MTD） 並評估毒性曲線和劑量限制性毒性（DLT）。identified in patients with refractory cancer Maximum tolerated dose (MTD) of AZD6738 when administered in combination with fixed-dose paclitaxel And assess the toxicity profile and dose-limiting toxicity (DLT). •       血液毒性如下： -    4級嗜中性白血球減少症持續超過連續4天。 -    在任何持續時間內伴有發燒 ≥ 38.5°C和/或全身感染的3級噬中性白血球減少症。 -    具有出血的3級血小板減少症。 -    ≥ CTCAEv4 4級的任何其他確定的血液學毒性。 •       ≥ CTCAEv4 3級的非血液學毒性，包括： -    實驗室異常。 -    QTc延長（＞ 500 mSec）。 •       任何其他大於基線處的並且臨床上重大和/或不可接受的和不響應支持性護理的毒性。 •       被SRC判定為DLT的任何事件，包括重大的劑量減少或遺漏。• Hematologic toxicity as follows: - Grade 4 neutropenia persisting for more than 4 consecutive days. - Grade 3 neutropenia with fever ≥ 38.5°C and/or systemic infection for any duration. - Grade 3 thrombocytopenia with bleeding. - Any other established hematologic toxicity ≥ CTCAEv4 grade 4. • Non-hematologic toxicities ≥ CTCAEv4 grade 3, including: - Laboratory abnormalities. - QTc prolongation (> 500 mSec). • Any other toxicity greater than baseline and clinically significant and/or unacceptable and not responsive to supportive care. • Any event judged by the SRC as a DLT, including major dose reductions or omissions.

次要目標和結果量度Secondary goals and outcome measures 次要目標secondary goal 結果量度Outcome measure 獲得 AZD6738與紫杉醇組合的抗腫瘤活性 的初步評估。get Antitumor activity of AZD6738 in combination with paclitaxel preliminary assessment. •       客觀反應率和臨床受益率（CR+PR+SD）。 •       藉由Kaplan-Meier法計算總存活期（OS）和無進展存活期（PFS）。• Objective response rate and clinical benefit rate (CR+PR+SD). • Overall survival (OS) and progression-free survival (PFS) were calculated by the Kaplan-Meier method. AZD6738，當以單一療法和與紫杉醇組合口服給藥時， 在單劑量後 和在多劑量給藥後的穩態下， 表徵其PK和藥效學（PDc）。AZD6738, when administered orally as monotherapy and in combination with paclitaxel, after a single dose and at steady state after multiple doses, Its PK and pharmacodynamics (PDc) were characterized. •       血漿和尿濃度以及得出的藥物動力學參數。• Plasma and urine concentrations and derived pharmacokinetic parameters. 獲得腫瘤中 AZD6738活性的初步評估acquired tumor Preliminary assessment of AZD6738 activity •       藉由評估藥效學生物標誌物變化，這可以包括功能ATR抑制、ctDNA和CTC。• By assessing changes in pharmacodynamic biomarkers, this can include functional ATR inhibition, ctDNA and CTCs.

第三目標和結果量度Third Objectives and Outcome Measures 第三目標third goal 結果量度Outcome measure 評估當AZD6738與固定劑量的紫杉醇組合給藥時，生物標誌物 對其的 敏感性和抗性。To assess biomarkers when AZD6738 is administered in combination with fixed-dose paclitaxel to it Sensitivity and resistance. •       回溯性定序以確定ATM無效突變亞群，探測性生物標誌物分析。 •       根據使用IHC得到的ATM表現和其他DNA修復相關的基因的突變狀態評估AZD6738的敏感性。 •       將藉由IHC評估ATM狀態。而且，將分析腫瘤處的全DDR基因，包括ATR。該等生物標誌物將用於預測對AZD6738與紫杉醇組合的敏感性。• Retrospective sequencing to identify subpopulations of ATM null mutants, exploratory biomarker analysis. • Sensitivity of AZD6738 was assessed based on ATM performance using IHC and the mutation status of other DNA repair-related genes. • ATM status will be assessed by IHC. Furthermore, the entire DDR gene at the tumor will be analyzed, including ATR. These biomarkers will be used to predict sensitivity to AZD6738 in combination with paclitaxel. 研究預測標誌物對AZD6738 與紫杉醇組合的敏感性或抗性， 該預期的標誌物可以在來自用AZD6738與紫杉醇組合治療的患者的腫瘤（存檔的和/或鮮凍的）中觀察到，以確定是否存在任何其他可預期對治療的敏感性或抗性的生物標誌物。進展性腫瘤樣本也將被收集用於探測性分析以確定對治療的獲得性抗性的機制。Investigating predictive markers for AZD6738 Sensitivity or resistance in combination with paclitaxel, This expected marker can be observed in tumors (archived and/or fresh frozen) from patients treated with AZD6738 in combination with paclitaxel to determine if there are any other predictable biomarkers of sensitivity or resistance to treatment thing. Progressive tumor samples will also be collected for exploratory analysis to determine mechanisms of acquired resistance to therapy. •       收集和儲存診斷的和/或存檔的腫瘤樣本和任何新鮮的腫瘤生檢（治療前和治療進行中），用於未來可能的對可能影響發展和/或對AZD6738與紫杉醇組合的反應的因素的探測性研究。將進行來自該等樣本的DNA的下一代定序和/或其他基於蛋白質的探測性分析。• Collection and storage of diagnostic and/or archived tumor samples and any fresh tumor biopsies (pre-treatment and treatment-in-progress) for possible future consideration of factors that may affect development and/or response to AZD6738 in combination with paclitaxel exploratory research. Next-generation sequencing and/or other protein-based exploratory analysis of DNA from these samples will be performed. 研究預測標誌物和 對AZD6738和/或紫杉醇的獲得性抗性，該等可能在提取自用AZD6738與紫杉醇的組合治療的病人的血液樣本的血漿製備物的循環腫瘤DNA（ctDNA）中觀察到。study predictive markers and Acquired resistance to AZD6738 and/or paclitaxel, which may be observed in circulating tumor DNA (ctDNA) in plasma preparations extracted from blood samples of patients treated with the combination of AZD6738 and paclitaxel. •       基因組方法（包括但不限於下一代定序和PCR）將用於未來的對能預測對AZD6738與紫杉醇組合的敏感性的因素的探測性研究。在治療過程中收集的樣本可以用於闡明對治療的抗性的機制。• Genomic approaches, including but not limited to next-generation sequencing and PCR, will be used for future probing studies of factors that predict sensitivity to AZD6738 in combination with paclitaxel. Samples collected during treatment can be used to elucidate mechanisms of resistance to treatment.

整體研究設計： 該研究由兩部分組成，每一部分評估當AZD6738與紫杉醇組合給藥時的安全性和耐受性。使用AZD6738的口服配製物。第一部分（A部分）與紫杉醇組合；在患有晚期實體惡性腫瘤的患者中，40 mg AZD6738 OD的開始劑量被遞增至達到最大耐受劑量，如劑量限制性毒性所定義的。我們進行了一系列的生檢以便基於出現的PK和PD之間的關係進一步探索在所選的一個或多個劑量下AZD6738的生物學活性。第二部分（B部分）係平行的PK擴展群組，其中週期0第1天給予AZD6738、（7天AZD6738洗脫期）第8至第21天單一療法（在紫杉醇組合之前），隨後從週期1開始伴有每週給予紫杉醇的組合療法。我們使該等群組的數量和劑量為彈性的以便當PK數據出現時我們能做出調整。第一部分係主要的臨床試驗。我們根據由其他正在進行的使用AZD6738的研究產生的數據做出改變以招募最小或最大數量的患者。在每一個群組中獨立地操作劑量遞增；然而，該等群組的數量和劑量將隨著PK數據的出現而接受改變。 Overall Study Design: The study consisted of two parts, each evaluating the safety and tolerability of AZD6738 when administered in combination with paclitaxel. Oral formulation of AZD6738 was used. The first part (Part A) was in combination with paclitaxel; in patients with advanced solid malignancies, the starting dose of 40 mg AZD6738 OD was escalated to the maximum tolerated dose, as defined by dose-limiting toxicities. We performed a series of biopsies to further explore the biological activity of AZD6738 at the selected dose or doses based on the emerging relationship between PK and PD. The second part (Part B) was a parallel PK expansion cohort in which AZD6738 was administered on day 1 of cycle 0, (7-day AZD6738 washout period) monotherapy on days 8 to 21 (before paclitaxel combination), followed by 1 Start combination therapy with weekly paclitaxel. We made the number and dose of these cohorts flexible so that we could make adjustments as PK data emerged. The first part is the main clinical trial. We made changes to recruit a minimum or maximum number of patients based on data generated from other ongoing studies using AZD6738. Dose escalation is performed independently in each cohort; however, the number and dose of such cohorts will be subject to change as PK data emerges.

A 部分 ：我們進行了I期試驗以確定在患有難治癌症的患者中，AZD6738與固定劑量的紫杉醇組合給藥時的最大耐受劑量（MTD）。在A部分中我們使用滾動6設計。治療時間表如下。開始方案（每4週）：40 mg OD給藥AZD6738，3週進行/1週停止；在第1天、第8天、第15天，紫杉醇80 mg/m2。這部分係與標準劑量的紫杉醇組合；在轉移性實體癌患者中，40 mg AZD6738 OD的開始劑量被遞增至達到最大耐受劑量。每個週期由4週組成。劑量遞增的決定係根據直到在第2週期的第1天投與研究藥物的時間收集的安全性和耐受性數據的評估做出的。選擇DLT評估期係因為導致在此類研究（血液學酶、胃腸道酶、肝臟酶）中劑量遞增停止的主要毒性有望在這段時期內呈現。AZD6738的劑量和/或時間表將由SRC定義。採用至少3個並且最多6個患者的群組大小（「滾動六設計」）以藉由減少對在DLT評估期變得不可評估的患者的後期代替的需要（同時不損害安全性數據的收集）來改善患者與接近假設治療劑量的群組的自然增長率。患者的總數量取決於所需的劑量調節的次數。該等患者具有視需要匹配的生檢以評估腫瘤的相關藥效學生物標誌物，並且進一步探索在該等劑量下的耐受性、安全性和藥物動力學活性。採用最多10個患者（最少2個患者）的群組大小。匹配的生檢定義為在基線、第7天和隨後疾病進展時的樣本（對於該試驗係視需要的）。 Part A : We conducted a phase I trial to determine the maximum tolerated dose (MTD) of AZD6738 in combination with fixed-dose paclitaxel in patients with refractory cancer. In Part A we use a scroll 6 design. The treatment schedule is as follows. Starting regimen (every 4 weeks): AZD6738 at 40 mg OD, 3 weeks on/1 week off; paclitaxel 80 mg/m2 on days 1, 8, and 15. This part was in combination with standard doses of paclitaxel; in patients with metastatic solid cancer, the starting dose of 40 mg AZD6738 OD was escalated to the maximum tolerated dose. Each cycle consists of 4 weeks. Dose escalation decisions were made based on an evaluation of safety and tolerability data collected up to the time of study drug administration on Day 1 of Cycle 2. The DLT evaluation period was chosen because the major toxicities leading to discontinuation of dose escalation in such studies (hematologic enzymes, gastrointestinal enzymes, liver enzymes) are expected to be present during this period. The dose and/or schedule of AZD6738 will be defined by the SRC. A cohort size of at least 3 and a maximum of 6 patients ("rolling six design") was employed to reduce the need for late substitution of patients who became non-evaluable during the DLT assessment period (while not compromising the collection of safety data) to improve the natural growth rate of patients with cohorts close to the hypothesized therapeutic dose. The total number of patients depends on the number of dose adjustments required. These patients have optionally matched biopsies to assess tumor-related pharmacodynamic biomarkers and further explore tolerability, safety, and pharmacokinetic activity at these doses. Cohort sizes of up to 10 patients (minimum of 2 patients) were used. Matched biopsies were defined as samples at baseline, Day 7, and subsequent disease progression (as needed for this test).

B 部分 ：平行PK拓展B部分用於評估藥物動力學。在開始B部分的第1週期（4週）之前，我們進行4週（第0週期）的單劑量AZD6738的藥物動力學評估。B部分係與標準劑量的紫杉醇組合；40 mg AZD6738 OD的起始劑量被遞增至藉由A部分獲得的最大耐受劑量。治療時間表如下。開始方案（每4週）：40 mg OD給藥AZD6738，3週進行/1週停止；在第1天、第8天、第15天，紫杉醇80 mg/m2。 Part B : Parallel PK Expansion Part B was used to assess pharmacokinetics. Before starting cycle 1 (week 4) of Part B, we performed a pharmacokinetic evaluation of a single dose of AZD6738 for 4 weeks (cycle 0). Part B was combined with standard doses of paclitaxel; the starting dose of 40 mg AZD6738 OD was escalated to the maximum tolerated dose obtained with Part A. The treatment schedule is as follows. Starting regimen (every 4 weeks): AZD6738 at 40 mg OD, 3 weeks on/1 week off; paclitaxel 80 mg/m2 on days 1, 8, and 15.

入選標準： 僅當以下所有入選標準適用且所有排除標準均不適用時，患者才有資格包括在研究中： 1.  在任何研究特定程序之前提供完全知情同意。 2.  年齡至少19歲。 3.  對標準護理化學療法已經失敗的難治性癌症患者。 4.  提供腫瘤樣本（來自切除術或生檢）。該標準對於該研究係視需要的（即，如果沒有生檢樣本，這不是排除標準）。 5.  在研究持續期間患者願意並且能夠遵守協議，包括經歷治療和計畫好的訪視和檢查。尤其是，對於所有劑量，患者從服藥前至少2小時至服藥後至少1小時必須禁食（僅可飲用水）。轉移性疾病或局部復發性疾病，其對已知提供臨床益處的現有一種或多種療法難治或不耐受。 6.  ECOG性能狀態0-1。 7.  患者的預期壽命從首次劑量起必須 ≥ 3個月。 8.  在基線和訪視時具有可以藉由成像被準確評估的至少一種可測量的病變。 9.  在28天的研究治療期內尿液或血清妊娠試驗呈陰性，這在治療之前確認。在開始給藥之前，有生育潛力的患者應該正在使用適當的避孕措施（兩種形式的高度可靠之方法），不應處於哺乳期並且妊娠測試必須呈陰性，或者患者必須已經具有無生育潛力的證據，即在篩選時滿足以下標準之一： (a) 絕經期後 - 定義為年齡超過50歲並且在所有外來激素治療停止後閉經至少12個月。 (b) 具有藉由子宮切除、雙側卵巢切除、或雙側輸卵管切除但非輸卵管結紮的不可逆的手術***的記錄。 (c) 閉經12個月並且血清濾泡刺激激素（FSH）、黃體化激素（LH）和血漿***水平在慣例的絕經後範圍內。 10.      如果性伴侶無生育潛力，男性患者必須願意在研究期間以及在最後劑量的研究藥物後的一週使用屏障避孕。 Inclusion Criteria: Patients were eligible for inclusion in the study only if all of the following inclusion criteria applied and all exclusion criteria did not apply: 1. Provided full informed consent prior to any study-specific procedures. 2. Be at least 19 years old. 3. Patients with refractory cancer who have failed standard-of-care chemotherapy. 4. Provide tumor samples (from resection or biopsy). This criterion is optional for the study department (ie, if no biopsy sample is available, this is not an exclusion criterion). 5. The patient is willing and able to comply with the protocol, including undergoing treatment and planned visits and examinations, for the duration of the study. In particular, for all doses, patients must fast (only drink water) from at least 2 hours before and at least 1 hour after. Metastatic disease or locally recurrent disease that is refractory or intolerant to one or more of the existing therapies known to provide clinical benefit. 6. ECOG performance status 0-1. 7. The patient's life expectancy must be ≥ 3 months from the first dose. 8. At least one measurable lesion that can be accurately assessed by imaging at baseline and visit. 9. A negative urine or serum pregnancy test during the 28-day study treatment period, which was confirmed prior to treatment. Before initiating dosing, patients of reproductive potential should be using appropriate contraception (both forms of highly reliable methods), should not be breastfeeding and must have a negative pregnancy test, or the patient must already be of non-fertile potential Evidence that one of the following criteria was met at screening: (a) Postmenopausal - defined as age over 50 years of age and amenorrhea for at least 12 months after cessation of all exogenous hormone therapy. (b) Documented irreversible surgical infertility by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation. (c) 12 months of amenorrhea and serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and plasma estradiol levels within the usual postmenopausal ranges. 10. Male patients must be willing to use barrier contraception during the study and for one week after the last dose of study drug if the sexual partner is non-fertile.

排除標準： 如果滿足以下排除標準中的任一項，那麼患者不進入研究： 1.  超過四種用於癌症治療的先前化學療法方案（排除輔助化學療法）。 2.  任何先前的用ATR抑制劑（小分子）進行的治療。 3.  任何先前的用紫杉醇進行的治療（如果在醫師的指導中，腫瘤對紫杉烷來說不是絕對難治的，則允許使用多西他賽）。 4.  患者具有第二原發癌，除了：充分治療的非黑色素瘤皮膚癌、有效治療的原位宮頸癌、或有效治療的且無疾病證據 ≤ 5年的其他實性瘤。 5.  患者不能吞咽口服投與的藥物。 6.  在招募前的最近14天期間（或更長時間段，取決於使用的藥劑的確定特徵）用任何研究性產品治療。 7.  從研究治療之前最後一劑的3週內（或更長的時期，取決於使用的藥劑的確定的特徵）接受任何全身性化療、放療（除了緩解疼痛原因之外）的患者。在研究之前和期間，患者可以接受穩定劑量的雙膦酸鹽或德索單抗（denusomab）用於治療骨轉移，如果該等係在治療之前至少4週開始的。 8.  伴隨使用已知的有效的CYP3A4抑制劑，例如酮康唑、伊曲康唑、利托那韋、茚地那韋、沙奎那韋、泰利黴素、克拉黴素、和奈非那韋。正在接受或已經接受顯著調節CYP3A4或Pgp活性的附隨藥物、草藥補充劑和/或食物（兩週的洗脫期，但對於聖約翰草（St. John’s Wort）係三週）。注意，該等包括普通的唑類抗真菌藥和大環內酯抗生素。 9.  除了脫髮，由先前的癌症治療引起的任何正在發生的毒性（＞CTCAE 1級）。 10.      在招募之前的4週內腸梗阻或CTCAE 3級或4級以上胃腸道出血。 11.      在24小時的時間段內在2個或更多個時間點處可測量的QTcF ＞ 470 msec的靜息ECG或長QT綜合症的家族史。 12.      具有如下心臟問題的患者：在開始治療之前的6個月內患有不受控制的高血壓或低血壓（儘管進行藥物治療，但BP ≥ 150/95 mmHg，BP ＜ 100/60 mmHg或下降在BP ＞ 20 mmHg的直立性低血壓）、超音波波心動描記法測量的左心室射血分數 ＜ 55%、在休息時ECG上的心室率 ＞ 100 bpm的心房纖顫、心臟衰竭症狀（NYHA II-IV級）、以前或現在患有心肌症、嚴重瓣膜性心臟病、不受控制的心絞痛（儘管進行藥物治療，但加拿大心血管學會II-IV級）、急性冠狀動脈綜合症。 13.      正在哺乳期或分娩期的女性患者。 14.      嚴重或不受控制的全身性疾病、活動性感染、活動性出血素質或腎移植的任何證據，包括已知已具有B型肝炎、C型肝炎或人體免疫缺陷病毒（HIV）的任何患者。 15.      共濟失調毛細血管擴張的診斷。 16.      骨髓儲備不足以及肝或腎功能損傷，如藉由以下任何一項化驗值所證明的： (a) 血紅蛋白 ＜ 9.0 g/dL（允許輸血） (b) 嗜中性球絕對計數（ANC）＜ 1.5 x 10 9 /L (c) 白血球（WBC）≤ 3 x 10 9 /L (d) 血小板計數 ＜ 100 x 10 9 /L（允許輸血） (e) 白蛋白 ＜ 33 g/L (f) 總膽紅素 ＜ 1.5 x 慣例的正常值上限（ULN） (g) AST（SGOT）/ALT（SGPT）＞ 2.5 x 慣例的正常值上限，除非存在肝轉移，在這種情況下，其必須 ＞ 5x ULN (h) 血清肌酸酐 ＞ 1.5 x 慣例的ULN (i) 腎小球濾過率（GFR）＜ 45 mL/min，如在研究中心使用標準方法學評估的（即Cockroft-Gault、MDRD或CKD-EPI公式、EDTA清除或24小時尿液採集）。 (j) 血尿：在顯微鏡檢查時或在試紙上呈+++ (k) INR ≥ 1.5或肝合成功能損傷的其他證據 Exclusion Criteria: Patients were not enrolled in the study if any of the following exclusion criteria were met: 1. More than four prior chemotherapy regimens for cancer treatment (excluding adjuvant chemotherapy). 2. Any previous treatment with an ATR inhibitor (small molecule). 3. Any prior treatment with paclitaxel (docetaxel is permitted if the tumor is not absolutely refractory to taxane as directed by the physician). 4. The patient has a second primary cancer, except for: adequately treated non-melanoma skin cancer, effectively treated in situ cervical cancer, or effectively treated other solid tumor with no evidence of disease ≤ 5 years. 5. The patient cannot swallow orally administered drugs. 6. Treatment with any investigational product during the last 14 days prior to enrolment (or a longer period depending on the established characteristics of the agent used). 7. Patients receiving any systemic chemotherapy, radiotherapy (other than pain relief) within 3 weeks (or longer, depending on the identified characteristics of the agent used) from the last dose prior to study treatment. Before and during the study, patients could receive stable doses of bisphosphonates or denusomab for the treatment of bone metastases, if these were started at least 4 weeks prior to treatment. 8. Concomitant use of known potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin, and nelfina Wei. Are receiving or have received concomitant drugs, herbal supplements, and/or foods that significantly modulate CYP3A4 or Pgp activity (two-week washout period, but three weeks for St. John's Wort). Note that these include common azole antifungals and macrolide antibiotics. 9. Any ongoing toxicity (>CTCAE grade 1) due to prior cancer therapy, other than alopecia. 10. Intestinal obstruction or CTCAE grade 3 or above gastrointestinal bleeding within 4 weeks prior to recruitment. 11. Resting ECG with measurable QTcF > 470 msec at 2 or more time points over a 24 hour period or family history of long QT syndrome. 12. Patients with the following cardiac problems: Uncontrolled hypertension or hypotension (BP ≥ 150/95 mmHg, BP < 100/60 mmHg or BP < 100/60 mmHg despite medication Orthostatic hypotension with a decrease in BP > 20 mmHg), left ventricular ejection fraction < 55% measured by echocardiography, atrial fibrillation with a ventricular rate > 100 bpm on ECG at rest, symptoms of heart failure ( NYHA class II-IV), previous or current cardiomyopathy, severe valvular heart disease, uncontrolled angina (Canadian Cardiovascular Society class II-IV despite medical therapy), acute coronary syndrome. 13. Female patients who are breastfeeding or giving birth. 14. Severe or uncontrolled systemic disease, active infection, active bleeding diathesis, or any evidence of kidney transplantation, including any patient known to have hepatitis B, hepatitis C, or human immunodeficiency virus (HIV). 15. Diagnosis of Ataxia Telangiectasia. 16. Inadequate bone marrow reserve and impairment of hepatic or renal function, as evidenced by any of the following assay values: (a) Hemoglobin < 9.0 g/dL (transfusion permitted) (b) Absolute Neutrophil Count (ANC) < 1.5 x 10 9 /L (c) White blood cells (WBC) ≤ 3 x 10 9 /L (d) Platelet count < 100 x 10 9 /L (transfusion allowed) (e) Albumin < 33 g/L (f) Total bilirubin < 1.5 x usual upper limit of normal (ULN) (g) AST(SGOT)/ALT(SGPT) > 2.5 x usual upper limit of normal unless liver metastases are present, in which case it must be > 5x ULN (h) Serum creatinine > 1.5 x conventional ULN (i) Glomerular filtration rate (GFR) < 45 mL/min, as assessed at the site using standard methodologies (ie, Cockroft-Gault, MDRD, or CKD -EPI formula, EDTA clearance, or 24-hour urine collection). (j) Hematuria: +++ on microscopic examination or on dipstick (k) INR ≥ 1.5 or other evidence of impaired hepatic synthesis

此外，以下被認為係從視需要的探索性宿主基因研究中排除的標準： 17.      先前的同種異體骨髓移植 18.      在基因樣本採集日的120天內非耗盡白血球的輸全血。In addition, the following are considered criteria for exclusion from optional exploratory host gene studies: 17. Previous Allogeneic Bone Marrow Transplantation 18. Whole blood transfusion that is not depleted of white blood cells within 120 days of the date of genetic sample collection.

研究治療： AZD6738藉由口服片劑與紫杉醇組合投與。對於所有劑量，患者從服藥前至少2小時至服藥後至少1小時必須禁食（僅可飲用水）。AZD6738由阿斯利康研發中心（AstraZeneca R&D）作為單瓶片劑提供。組合藥劑由當地來源提供（直接地或有償的當地供應）。根據由阿斯利康研發中心制定的藥品生產品質管制規範和當地管理指南來製備標籤。所有研究藥物在合適的儲存條件下保存在安全的地方。瓶上的AZD6738和組合藥劑產品標籤指定合適的儲存方式。 Study Treatment: AZD6738 was administered by oral tablet in combination with paclitaxel. For all doses, patients must fast (only water) from at least 2 hours before and at least 1 hour after. AZD6738 is offered as a single vial tablet by AstraZeneca R&D. Combinations are provided from local sources (direct or paid local supply). Labels were prepared in accordance with Good Manufacturing Practice and local regulatory guidelines developed by AstraZeneca R&D. All study drugs are kept in a safe place under appropriate storage conditions. AZD6738 and the combination drug product label on the bottle specifies appropriate storage.

AZD6738的起始劑量/時間表係在4週（28天）的週期中，21天每天40 mg OD、隨後7天治療停止。研究以A部分（紫杉醇組合）開始，其中使用所選的每日一次40 mg AZD6738的起始劑量。對於所有劑量，患者從服藥前至少2小時至服藥後至少1小時必須禁食（僅可飲用水）。在第一週期之前，患者在第一天（第0週期第1天）接受單次劑量以評估PK，然後6天不接受研究藥物。然後，在第1週期第1天、第8天和第15天投與紫杉醇，同時從每個為期28天的週期的第1天至第21天再引入每天一次AZD6738。根據出現的安全性和耐受性數據決定其他部分的起始劑量/時間表。The starting dose/schedule of AZD6738 is based on a 4-week (28-day) cycle of 40 mg OD per day for 21 days followed by 7 days of treatment discontinuation. The study started with Part A (paclitaxel combination) with a selected starting dose of AZD6738 of 40 mg once daily. For all doses, patients must fast (only water) from at least 2 hours before and at least 1 hour after. Prior to Cycle 1, patients received a single dose on Day 1 (Day 1 of Cycle 0) to assess PK and then received no study drug for 6 days. Then, paclitaxel was administered on days 1, 8, and 15 of cycle 1, while AZD6738 was reintroduced once daily from days 1 to 21 of each 28-day cycle. The starting dose/schedule for the other parts will be determined based on emerging safety and tolerability data.

響應於安全性、耐受性、藥物動力學和出現的非臨床數據，增加或降低在隨後的群組中的每日劑量、劑量頻率和給藥時間表。劑量遞增和遞減遵循以下方案，根據以下邏輯： (a) 如果在3名可評估的患者的群組中沒有觀察到劑量限制性毒性（DLT），那麼可以進行劑量遞增。在對來自最少3名可評估的患者的數據進行審查後，將允許劑量增加。 (b) 如果在3名或更多名可評估的患者的組中一名患者經歷了DLT，那麼該群組將被擴展到包括6名可評估的患者。如果在6名可評估的患者的完整群組中只觀察到一例DLT，那麼可以進行劑量遞增。 (c) 如果在至多6名可評估的患者的群組中2名或更多名患者經歷DLT，那麼不論入組患者的數量如何，將認為劑量不被耐受並且對該群組的招募和劑量遞增將停止。可以考慮更低的中間劑量（遞減）以便更好地定義MTD。The daily dose, dose frequency, and dosing schedule in subsequent cohorts were increased or decreased in response to safety, tolerability, pharmacokinetics, and emerging nonclinical data. Dose escalation and decrement follow the following schedule, according to the following logic: (a) If no dose-limiting toxicity (DLT) is observed in the cohort of 3 evaluable patients, then dose escalation may be performed. Dose escalation will be permitted after review of data from a minimum of 3 evaluable patients. (b) If one patient in a cohort of 3 or more evaluable patients experienced DLT, the cohort will be expanded to include 6 evaluable patients. If only one DLT is observed in the complete cohort of 6 evaluable patients, dose escalation can be performed. (c) If 2 or more patients in a cohort of up to 6 evaluable patients experience DLT, then regardless of the number of patients enrolled, the dose will be considered intolerable and recruitment and Dose escalation will stop. A lower intermediate dose (decrease) can be considered to better define the MTD.

在來自一個群組的最後一名可評估的患者完成給藥與隨後群組中開始給藥之間沒有最少時間期限的要求。沒有患者內劑量遞增。在研究的劑量遞增期過程中每次劑量水平之後，研究者評估AZD6738的安全性和耐受性和藥物動力學以決定下一劑量和/或時間表。There is no minimum time period required between the completion of dosing by the last evaluable patient from a cohort and the initiation of dosing in subsequent cohorts. There were no intra-patient dose escalation. Following each dose level during the dose escalation phase of the study, the investigator evaluates the safety and tolerability and pharmacokinetics of AZD6738 to determine the next dose and/or schedule.

基於出現的數據，由SRC做出以改變下一群組的任何決定如下： (a) 響應於出現的耐受性數據來修改AZD6738*的劑量、每日劑量頻率或時間表以在給定的週期內增加、維持或減少AZD6738的暴露； (b) 如果研究者認為該劑量係被耐受的，則遞增AZD6738的劑量；或 (c) 如果研究者認為該劑量不被耐受，則以特定的時間表遞減AZD6738的劑量（針對高於20 mg的劑量）至先前更低的劑量水平（至多6名可評估患者的最大值）或至中間的更低劑量水平；或 (d) 如果研究者認為目前的時間表係非耐受的，則對紫杉醇劑量後停止用AZD6738治療的時間增加額外的天數，同時相應減少用AZD 6738的治療天數；或 (e) 基於出現的數據增加第一週期紫杉醇之前停止用AZD6738治療的時間； (f) 取決於出現的數據增加AZD6738的每日劑量頻率；或 (g) 取決於出現的數據減小AZD6738的每日劑量頻率Based on the data presented, any decisions made by the SRC to change the next cohort are as follows: (a) modifying the dose, daily dose frequency, or schedule of AZD6738* in response to emerging tolerability data to increase, maintain, or decrease exposure to AZD6738 over a given cycle; (b) escalate the dose of AZD6738 if the investigator believes the dose is tolerable; or (c) Decrease the dose of AZD6738 on a specified schedule (for doses above 20 mg) to a previously lower dose level (maximum of up to 6 evaluable patients) if the investigator believes the dose is not tolerated ) or to an intermediate lower dose level; or (d) if the investigator believes that the current schedule is not tolerated, add an additional number of days to the time to discontinue treatment with AZD6738 after the paclitaxel dose, with a corresponding reduction in the number of days of treatment with AZD6738; or (e) increasing the time to discontinue treatment with AZD6738 before the first cycle of paclitaxel based on emerging data; (f) increase the frequency of daily doses of AZD6738 depending on emerging data; or (g) Decrease daily dose frequency of AZD6738 depending on emerging data

在連續的群組之間可能發生對以下參數中的僅2種的改變： (h) AZD6738的劑量。 (i) AZD6738的每日劑量頻率。 (j) AZD6738的時間表。 然而，與先前最大耐受總週期劑量相比，總週期劑量或預測的Cmax增加不超過2倍。紫杉醇時間表和劑量係固定的。Changes to only 2 of the following parameters may occur between consecutive groups: (h) Dosage of AZD6738. (i) Daily dose frequency of AZD6738. (j) Timeline of AZD6738. However, the total cycle dose or predicted Cmax did not increase more than 2-fold compared to the previous maximum tolerated total cycle dose. The paclitaxel schedule and dose were fixed.

劑量限制性毒性（ DLT ） ：如果至多6名可評估的患者中的2名或更多名在一個劑量水平經歷DLT，那麼認為該劑量係不被耐受的並且劑量遞增停止。一旦不被耐受的劑量被確定，MTD將被確認為低於該不被耐受的劑量的先前的劑量水平或者將研究在該不被耐受的劑量和最後耐受的劑量之間的劑量。需要六名可評估的患者來確定MTD。 Dose-Limiting Toxicity ( DLT ) : If 2 or more of up to 6 evaluable patients experienced DLT at a dose level, the dose was considered to be intolerable and dose escalation was discontinued. Once the intolerable dose is determined, the MTD will be confirmed as a previous dose level below the intolerable dose or doses between the intolerable dose and the last tolerated dose will be investigated . Six evaluable patients were required to determine MTD.

DLT被定義為在第0週期（單一療法）和第1週期（組合）時間段的期間（即，從第0週期的第1天給藥直到第1週期的最後一天給藥）的任意毒性，這包括： (a) 如下的血液毒性： -   4級嗜中性白血球減少症（ANC ＜ 500個細胞/mm3）持續超過連續4天 -   在任何持續時間內伴有發燒 ≥ 38.5°C和/或全身感染的3級噬中性白血球減少症（ANC ≥ 500至 ＜ 1000個細胞/mm3）。 -   伴有出血的3級血小板減少症（25,000至 ＜ 50,000/mm3）。 -   ≥CTCAEv4 4級的任何其他確定的血液學毒性（可能需要重複以在缺乏臨床體征、症狀或其他異常調查時確定孤立性異常，即受懷疑的虛假值）。 (b) ≥ CTCAEv4 3級的非血液學毒性，包括： -   實驗室異常（可能需要重複以在缺乏臨床體征、症狀或其他異常調查時確定孤立性異常，即受懷疑的虛假值）。 -   QTc延長（＞ 500 msec）。 (c) 任何其他大於基線處的並且臨床上重大和/或不可接受的和不響應於支持性護理的毒性。 (d) 被SRC判定為DLT的任何事件，包括重大的劑量減少或遺漏。 (e) 排除的DLT： -   任何級別的脫髮。 -   未充分治療的3級噁心和/或嘔吐和3級腹瀉（任何此類患者應該已經接受最佳止吐和/或止瀉預防和/或治療）。 -   明顯與AZD6738/卡鉑組合無關的任何毒性，例如研究中僅與疾病有關的或疾病相關的過程。DLT was defined as any toxicity during the period of Cycle 0 (monotherapy) and Cycle 1 (combination) time periods (ie, from dosing on Day 1 of Cycle 0 until dosing on the last day of Cycle 1), This includes: (a) Hematological toxicity as follows: - Grade 4 neutropenia (ANC < 500 cells/mm3) for more than 4 consecutive days - Grade 3 neutropenia (ANC ≥ 500 to < 1000 cells/mm3) with fever ≥ 38.5°C and/or systemic infection for any duration. - Grade 3 thrombocytopenia with bleeding (25,000 to < 50,000/mm3). - Any other established hematologic toxicity of ≥CTCAEv4 grade 4 (may need to be repeated to identify an isolated abnormality in the absence of investigation of clinical signs, symptoms or other abnormalities, i.e. suspected spurious values). (b) Non-hematologic toxicities ≥ CTCAEv4 grade 3, including: - Laboratory abnormalities (may need to be repeated to identify isolated abnormalities, i.e. suspected spurious values, in the absence of investigation of clinical signs, symptoms or other abnormalities). - QTc prolongation (> 500 msec). (c) Any other toxicity greater than baseline and clinically significant and/or unacceptable and not responsive to supportive care. (d) Any event judged by the SRC as a DLT, including major dose reductions or omissions. (e) Excluded DLTs: - Any level of hair loss. - Inadequately treated grade 3 nausea and/or vomiting and grade 3 diarrhea (any such patient should have received optimal antiemetic and/or antidiarrheal prophylaxis and/or treatment). - Any toxicity not clearly related to the AZD6738/carboplatin combination, such as only disease-related or disease-related processes in the study.

功效評估 ：該研究評估了AZD6738在與紫杉醇組合給藥時在患有轉移性實體癌症的患者中的功效。藉由確定PFS和ORR，使用RECIST 1.1標準來評估患者對治療的反應。RECIST 1.1指南用於可測定的、不可測定的、靶和非靶病變以及客觀腫瘤反應標準（完全反應、部分反應、穩定疾病或疾病的進展）。在基線處使用腫瘤負擔的評估方法，在每次隨後的跟蹤評估時使用胸、腹部和骨盆的CT或MRI掃描。在基線評估後，藉由每8週（相對於第一劑量的日期）進行客觀腫瘤評估來評估對所有患者的功效，直到第40週，此時每12週進行評估直到如RECIST 1.1定義的客觀疾病進展。Efficacy evaluation : This study evaluated the efficacy of AZD6738 in patients with metastatic solid cancer when administered in combination with paclitaxel. RECIST 1.1 criteria were used to assess patient response to treatment by determining PFS and ORR. RECIST 1.1 guidelines are used for measurable, non-measurable, target and non-target lesions, and objective tumor response criteria (complete response, partial response, stable disease, or disease progression). Tumor burden assessments were used at baseline, and CT or MRI scans of the chest, abdomen, and pelvis were used at each subsequent follow-up assessment. Efficacy in all patients was assessed by objective tumor assessment every 8 weeks (relative to the date of the first dose) after the baseline assessment until week 40, at which time assessments were performed every 12 weeks until objective as defined in RECIST 1.1 Disease progression.

如果患者在進展前中斷治療（和/或接受隨後的癌症療法），那麼該患者將被繼續跟蹤直到如RECIST 1.1定義的客觀疾病進展。If a patient discontinued treatment (and/or received subsequent cancer therapy) prior to progression, the patient will continue to be followed until objective disease progression as defined by RECIST 1.1.

客觀腫瘤反應評估的分類基於RECIST 1.1反應標準：CR（完全反應）、PR（部分反應）、SD（穩定疾病）和PD（疾病進展）。相比於當腫瘤負擔處於最小（即,研究中以前記錄的最小直徑之和）時來計算靶標病變（TL）進展。在沒有進展時，相比於開始治療之前獲得的基線腫瘤測量值來計算腫瘤反應（CR、PR、SD）。Classification of objective tumor response assessments was based on RECIST 1.1 response criteria: CR (complete response), PR (partial response), SD (stable disease), and PD (progressive disease). Target lesion (TL) progression was calculated compared to when tumor burden was at a minimum (ie, the sum of the smallest diameters previously recorded in the study). In the absence of progression, tumor response (CR, PR, SD) was calculated compared to baseline tumor measurements obtained prior to initiation of treatment.

對於任何在基線處具有不可測量的疾病的患者，客觀腫瘤反應評估的分類基於RECIST 1.1反應標準：CR、PD和非CR/非PD。如果研究者不確定進展是否已經發生，特別是對NTL（非靶病變）的反應或出現新病變情況下，建議繼續進行治療直到下一個預定評估或更早（如果有臨床指征）並重新評估受試者的狀態。如果重複掃描確定進展，那麼初始掃描的日期將被宣佈為進展日期。For any patient with unmeasurable disease at baseline, classification of objective tumor response assessments was based on RECIST 1.1 response criteria: CR, PD, and non-CR/non-PD. If the investigator is unsure whether progression has occurred, especially in response to NTL (non-target lesions) or new lesions, it is recommended to continue treatment until the next scheduled assessment or earlier (if clinically indicated) and reassess Subject's status. If repeated scans determine progress, the date of the initial scan will be declared the progress date.

懷疑有新疾病的任何其他位置也應進行適當成像。如果執行計畫外的評估並且患者還未進展，則應在計畫訪視時儘量嘗試執行後續評估。為了在非靶疾病的基礎上實現‘明確的進展’，非靶疾病的整體水平必須嚴重惡化，以便即使在靶疾病中存在SD或PR的情況下，總體腫瘤負荷也已增加足以值得中止療法。一個或多個非靶病變的大小的適度地「增加」通常不足以證明明確的進展狀態。Any other locations where new disease is suspected should also be properly imaged. If an unscheduled evaluation is performed and the patient has not progressed, an attempt should be made to perform a follow-up evaluation at the planned visit as much as possible. To achieve 'definitive progression' on the basis of off-target disease, the overall level of off-target disease must be severely worsened so that even in the presence of SD or PR in target disease, the overall tumor burden has increased enough to warrant discontinuation of therapy. A modest "increase" in the size of one or more non-target lesions is usually not sufficient to demonstrate a definitive progression status.

在進展後，繼續跟蹤患者數週，如研究時間表所概述的（參見表1）。盡可能貼近地遵循評估時間表係重要的。Following progression, patients were continued to be followed for several weeks, as outlined in the study schedule (see Table 1). It is important to follow the assessment schedule as closely as possible.

安全性和臨床評估 ：AZD6738的安全性和耐受性係本研究的主要目標。相關的結局指標係DLT、AE/SAE、生命體征、臨床化學/血液學和ECG。實驗室安全評估包括： Safety and Clinical Evaluation : The safety and tolerability of AZD6738 are the primary objectives of this study. Relevant outcome measures were DLT, AE/SAE, vital signs, clinical chemistry/hematology, and ECG. Laboratory safety assessments include:

全血液學評估： (a) 血紅蛋白。 (b) 紅血球（RBC）。 (c) 血小板。 (d) 平均細胞體積（MCV）。 (e) 平均細胞血紅蛋白濃度（MCHC）。 (f) 平均細胞血紅蛋白（MCH）。 (g) WBC。 (h) 在每次訪視和當臨床指征時採取差異白血球絕對計數（嗜中性球、淋巴細胞、單核細胞、嗜酸性粒細胞和嗜鹼粒細胞）和絕對嗜中性球計數或分段嗜中性白血球數以及帶形。如果絕對差異不可用，將提供%差異。 (i) 凝血： -   在基線處和如果臨床指征的話進行活化部分凝血活酶時間（APTT） -   在基線處和如果臨床指征的話進行國際標準化比率（INR），除非患者正接受華法林。服用華法林的患者能參加該研究；然而，建議每週至少一次仔細監測凝血酶原時間（INR和APTT）持續第一個月，然後如果INR穩定的話每月進行監測。 (j) 安全性的生化評估： -   鈉 -   鉀 -   鈣 -   鎂 -   肌酸酐 -   總膽紅素 -   γ穀胺醯轉移酶（GGT） -   ALP -   AST -   ALT -   尿素或血尿素氮（BUN） -   總蛋白質 -   白蛋白 -   乳酸脫氫酶（LDH）。Complete hematology evaluation: (a) Hemoglobin. (b) Red blood cells (RBCs). (c) Platelets. (d) Mean cell volume (MCV). (e) Mean cellular hemoglobin concentration (MCHC). (f) Mean cellular hemoglobin (MCH). (g) WBC. (h) Different absolute white blood cell counts (neutrophils, lymphocytes, monocytes, eosinophils and basophils) and absolute neutrophil counts at each visit and when clinically indicated or Segmented neutrophil count and band shape. If absolute difference is not available, % difference will be provided. (i) Coagulation: - Activated partial thromboplastin time (APTT) at baseline and if clinically indicated - International Normalized Ratio (INR) at baseline and if clinically indicated, unless the patient is receiving warfarin. Patients taking warfarin can participate in the study; however, careful monitoring of prothrombin time (INR and APTT) at least weekly for the first month and then monthly if the INR is stable is recommended. (j) Biochemical assessment of safety: - Sodium - Potassium - calcium - Magnesium - Creatinine - Total bilirubin - Gamma glutamine transferase (GGT) - ALP - AST - ALT - Urea or blood urea nitrogen (BUN) - total protein - Albumin - Lactate dehydrogenase (LDH).

尿液分析：在篩選時以及如果臨床指征的話進行尿液分析。如果需要，將由醫院的當地實驗室進行顯微鏡分析。如果在第一劑量之前7天內被評估並且符合所述之資格標準（如果適用），不需要在第1週期的第1天進行重複，除非研究者認為其可能已經顯著發生變化。Urinalysis: Perform urinalysis at screening and if clinically indicated. If required, microscopic analysis will be performed by the hospital's local laboratory. If assessed within 7 days prior to the first dose and met the eligibility criteria described (if applicable), repeats on Day 1 of Cycle 1 are not required unless the investigator believes it may have changed significantly.

體格檢查將進行全面的體格檢查，包括以下方面的評估：一般外貌、呼吸、心血管、腹部、皮膚、頭和頸（包括耳、眼、鼻和喉）、淋巴結、甲狀腺、腹部、骨骼肌（包括脊柱和四肢）和神經系統。在篩選時以及如研究時間表所概括的使用ECOG標度評估表現狀態。每次將由相同的觀察者來評估表現狀態。如果在第一劑量之前7天內被評估並且符合所述之資格標準（如果適用），不需要在第1週期的第1天進行重複，除非研究者認為其可能已經顯著發生變化。Physical Examination A comprehensive physical examination will be performed, including evaluation of the following: general appearance, respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, abdomen, skeletal muscles ( including spine and extremities) and nervous system. Performance status was assessed using the ECOG scale at screening and as outlined in the study schedule. Performance status will be assessed by the same observer each time. If assessed within 7 days prior to the first dose and met the eligibility criteria described (if applicable), repeats on Day 1 of Cycle 1 are not required unless the investigator believes it may have changed significantly.

ECG：在開始研究治療之前7天內、當臨床指征時和在患者中止研究用藥後的跟蹤時，需要ECG。在每種情況下，在患者已經在仰臥位置休息至少5分鐘後獲得十二導聯心電圖。當患者在仰臥位置時將記錄所有十二導聯心電圖。研究者或指定的醫生在定時的十二導聯心電圖被收集時的每個研究日將再審查它們的紙質複本。ECG將以25 mm/sec記錄。所有的ECG將被研究者評估它們是否係臨床上顯著異常的/非臨床上顯著異常的。如果發現係臨床上顯著異常，研究者將其在CRF上記錄為AE。顯示研究數量和電子代碼的ECG的複本將包括在研究檔中。ECG: ECG is required within 7 days prior to initiation of study treatment, when clinically indicated, and at follow-up after patient discontinuation of study medication. In each case, a twelve-lead electrocardiogram was obtained after the patient had rested in a supine position for at least 5 minutes. All twelve-lead ECGs will be recorded while the patient is in the supine position. Paper copies of timed twelve-lead ECGs will be reviewed by the investigator or designated physician each study day when they are collected. ECG will be recorded at 25 mm/sec. All ECGs will be assessed by the investigator for whether they are clinically significant/non-clinically significant. If a clinically significant abnormality was found, the investigator recorded it as an AE on the CRF. A copy of the ECG showing the study number and electronic code will be included in the study file.

生命體征：身高僅在篩選時評估。體重在篩選時和如臨床指征的任何其他時間評估。如果適用，生命體征的任何變化將被記錄為AE。在患者休息至少10分鐘後，將使用具有合適袖口尺寸的半自動BP記錄設備來測量仰臥BP和脈搏率，並且將在第0週期的第1天和第1週期的第1天、第8天、第15天進行評估，然後每個週期進行。（在預定日期 +/- 7天窗口內）。監測直立性低血壓。在合適的CRF上記錄採集和測量的日期和時間。在篩選時和如臨床指征的任何其他時間使用自動溫度計測量體溫（以攝氏度計）。在合適的CRF上記錄採集和測量的日期。Vital Signs: Height was assessed only at screening. Body weight was assessed at screening and at any other time as clinically indicated. If applicable, any changes in vital signs will be recorded as AEs. Supine BP and pulse rate will be measured using a semi-automatic BP recording device with an appropriate cuff size after the patient has rested for at least 10 minutes, and will be measured on Day 1 of Cycle 0 and Days 1, 8, 1 of Cycle 1, Assessments are performed on day 15 and then every cycle. (within the scheduled date +/- 7 days window). Monitor for orthostatic hypotension. Record the date and time of acquisition and measurement on the appropriate CRF. Use an automatic thermometer to measure body temperature (in degrees Celsius) at screening and at any other time as clinically indicated. Record the date of acquisition and measurement on the appropriate CRF.

其他安全性評估：對任何具有生育潛力的絕經期前女性進行兩次血液樣本或尿樣的妊娠試驗，一次在研究治療開始前的28天內，並且另一次在開始治療之前研究的第1天。試驗將由醫院的當地實驗室進行。如果結果係陽性的，患者將不具備研究資格/中止研究。Additional Safety Assessments: Two pregnancy tests with blood or urine samples in any premenopausal woman of reproductive potential, one within 28 days prior to the start of study treatment and the other on Study Day 1 prior to initiation of treatment . Trials will be conducted by the hospital's local laboratory. If the result is positive, the patient will be disqualified/discontinued from the study.

伴隨用藥： 在研究者的判斷下，給予任何被認為係受試者的福利所必需的並且不會干擾試驗用藥的藥物（除了被臨床試驗方案排除的那些藥物）。研究者將在CRF的合適部分記錄在試驗期間（從簽署知情同意書的那天開始）受試者服用的所有伴隨用藥。 Concomitant Medication: Administer, at the discretion of the Investigator, any medication deemed necessary for the welfare of the subject and which will not interfere with the investigational medication (other than those excluded by the clinical trial protocol). The investigator will record all concomitant medications taken by the subject during the trial period (starting on the day of signing the informed consent form) in the appropriate section of the CRF.

在試驗期間，以下各項係不允許的： (a) 預防性的粒細胞群落刺激因子或粒細胞巨噬細胞群落刺激因子。 (b) 伴隨使用已知的有效的CYP3A4抑制劑，例如酮康唑、伊曲康唑、利托那韋、茚地那韋、沙奎那韋、泰利黴素、克拉黴素、和奈非那韋。 (c) 為了避免由於藥物相互作用造成的可能的暴露減少，應避免以下CYP3A4誘導劑：苯妥英、利福平、利福噴汀、利福布汀、卡馬西平、***、奈韋拉平、莫達非尼和聖約翰草。 (d) 具有批准的抗癌指示的中藥。During the test, the following are not allowed: (a) Prophylactic granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor. (b) Concomitant use of known potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin, and nefi Nave. (c) To avoid possible exposure reductions due to drug interactions, the following CYP3A4 inducers should be avoided: phenytoin, rifampicin, rifapentine, rifabutin, carbamazepine, phenobarbital, nevirapine, Modafinil and St. John's Wort. (d) Chinese medicines with approved anti-cancer indications.

藥物動力學 ：在A、B部分的第0週期，獲取靜脈血樣本（2 mL）用於確定血漿中AZD6738和相關活性代謝物的濃度。記錄每個樣本的採集日期和時間。在A部分的第0週期（平行PK拓展研究）中，每個群組在指定PK位點最少招募6名患者。在A、B部分的第1週期，在提出的時間獲取靜脈血樣本（4 mL）用於確定血漿中AZD6738和AZ13368982（活性代謝物）或紫杉醇的濃度和代謝物的表徵。將記錄每個樣本的採集日期和時間。樣本將被分開，一部分用於AZD6738和相關活性代謝物並且另一份用於代謝物鑒定工作。 Pharmacokinetics : During Cycle 0 of Parts A and B, venous blood samples (2 mL) were obtained for the determination of plasma concentrations of AZD6738 and related active metabolites. Record the date and time of collection for each sample. In Cycle 0 of Part A (parallel PK extension study), a minimum of 6 patients were recruited per cohort at the indicated PK locus. In Cycle 1 of Parts A and B, venous blood samples (4 mL) were obtained at the indicated times for determination of plasma concentrations of AZD6738 and AZ13368982 (active metabolites) or paclitaxel and metabolite characterization. The date and time of collection for each sample will be recorded. Samples will be split, one for AZD6738 and related active metabolites and another for metabolite identification work.

使用合適的生物分析法來分析樣本以確定AZD6738和活性代謝物在血漿中的濃度和AZD6738在尿液中的濃度和紫杉醇在血漿中的濃度。在生物分析實驗室接收時，所有仍在目的分析物（即AZD6738或紫杉醇）的已知穩定性範圍內的樣本都將進行分析。此外，藥物動力學樣本可能已經進行進一步分析以便進一步研究藥物代謝物的存在和/或屬性。此類分析的任何結果將與臨床研究報告分開報告。The samples are analyzed using an appropriate bioassay to determine the plasma concentrations of AZD6738 and the active metabolite and the urine concentrations of AZD6738 and the paclitaxel concentrations in plasma. All samples still within the known stability range of the analyte of interest (ie AZD6738 or paclitaxel) will be analyzed upon receipt in the bioanalytical laboratory. In addition, pharmacokinetic samples may have undergone further analysis to further investigate the presence and/or properties of drug metabolites. Any results of such analyses will be reported separately from the clinical study report.

藥效學 ：藥效學（PDc）生物標誌物係本研究的關鍵次要目標並且用於告知在具有AGC的患者中用AZD6738治療後ATR靶抑制的程度和持續時間。PDc生物標誌物分析還用於獲得患者中AZD6738 PK-PD關係的初始評估並確定與ATM狀態和對AZD6738治療的反應的任何回溯關聯。 Pharmacodynamics : Pharmacodynamic (PDc) biomarkers were a key secondary objective of this study and were used to inform the extent and duration of ATR target inhibition following treatment with AZD6738 in patients with AGC. PDc biomarker analysis was also used to obtain an initial assessment of the AZD6738 PK-PD relationship in patients and to identify any retrospective associations with ATM status and response to AZD6738 treatment.

生物標誌物： 對於該I期試驗，基於血液的PDc生物標誌物樣本的採集係強制的。收集外周血樣本並分析以對ATR途徑生物標誌物進行下游分析，在純化的外周血單核細胞（PBMC）樣本中，ATR途徑生物標誌物可以包括但不限於γ-H2AX、pCHK、pATR。如研究計畫中的詳述收集外週血（10 mL），如果訪視發生在週末，則波動為 +/- 1天。用於生物標誌物分析的血液、存檔的和鮮凍的組織的採集、樣本的運送和儲存的其他細節可在實驗室手冊中找到。 Biomarkers: For this Phase I trial, collection of blood-based PDc biomarker samples was mandatory. Peripheral blood samples are collected and analyzed for downstream analysis of ATR pathway biomarkers, in purified peripheral blood mononuclear cell (PBMC) samples, ATR pathway biomarkers can include but are not limited to γ-H2AX, pCHK, pATR. Peripheral blood (10 mL) was collected as detailed in the study plan, with fluctuations of +/- 1 day if visits occurred on weekends. Additional details on collection of blood, archived and frozen tissue, sample shipping and storage for biomarker analysis can be found in the laboratory manual.

對於所有患者，要求包埋在石蠟塊中的福馬林固定的腫瘤組織。如果還可以收集基線生檢樣本，則仍高度鼓勵取回存檔診斷腫瘤材料，以提供自診斷以來腫瘤如何演變的數據。接受來自原發性腫瘤或轉移性腫瘤的存檔樣本，但是來自原發性腫瘤的組織係較佳的。來自最近的生檢的組織係較佳的，其中患者具有來自多個時間點的存檔組織樣本。如果腫瘤塊不能提交，則接受新鮮製備的未染色的載玻片（最少10個，較佳的是20個）、來自存檔的腫瘤塊的4個微切片，然而腫瘤組織塊係較佳的。 收集10 mL外周血樣本以提供血漿用於循環腫瘤DNA，分析預測生物標誌物，並詢查遺傳改變的變化和對AZD6738治療具有抗性的潛在機制。在以下時間點收集用於ctDNA的血液樣本：治療前第0週期第1天、第1週期第1天和每個週期第1天、以及治療中止時。臨床試驗結果 Formalin-fixed tumor tissue embedded in paraffin blocks was required for all patients. If baseline biopsies can also be collected, retrieval of archived diagnostic tumor material to provide data on how the tumor has evolved since diagnosis is still highly encouraged. Archived samples from primary or metastatic tumors are accepted, but tissue lines from primary tumors are preferred. Tissue lines from recent biopsies are preferred, where the patient has archived tissue samples from multiple time points. If the tumor mass cannot be submitted, freshly prepared unstained slides (minimum 10, preferably 20), 4 microsections from the archived tumor mass are accepted, however tumor tissue mass is preferred. A 10 mL peripheral blood sample was collected to provide plasma for circulating tumor DNA, analyzed for predictive biomarkers, and interrogated for changes in genetic alterations and underlying mechanisms of resistance to AZD6738 treatment. Blood samples for ctDNA were collected at the following time points: day 1 of cycle 0 before treatment, day 1 of cycle 1 and day 1 of each cycle, and when treatment was discontinued. Clinical Trial Results

為了使患者對於DLT評估係可評估的，他們必須在第1週期期間已經接受至少75%指定劑量的賽拉雷澤替博、或在相同時間段期間經歷了DLT。根據RECIST 1.1標準、使用電腦斷層成像每兩個週期評估腫瘤反應持續前10個週期，隨後每3個週期進行評估直到進展。In order for a patient to be evaluable for DLT assessment, they must have received at least 75% of the indicated dose of xelarazepate during Cycle 1, or experienced a DLT during the same time period. Tumor response was assessed every two cycles using computed tomography according to RECIST 1.1 criteria for the first 10 cycles and every 3 cycles thereafter until progression.

根據以上方案在臨床試驗中招募57名患者（33名黑色素瘤患者、15名胃癌（GC）患者、4名肉瘤患者、3名大腸癌患者、1名神經內分泌癌患者和1名肝細胞癌患者），包括從40 mg OD至240 mg BID的7個劑量群組。以AZD6738 160 mg BD和240 mg BD（第1-14天）的n = 6名可評估患者的每個群組中發生一例中性粒細胞減少症發熱的劑量限制性毒性（DLT）。根據方案，AZD6738的最大耐受劑量係240 mg BID（第1-14天）。57 patients (33 patients with melanoma, 15 patients with gastric cancer (GC), 4 patients with sarcoma, 3 patients with colorectal cancer, 1 patient with neuroendocrine cancer and 1 patient with hepatocellular carcinoma were enrolled in the clinical trial according to the above protocol ), including 7 dose cohorts from 40 mg OD to 240 mg BID. One dose-limiting toxicity (DLT) of neutropenic fever occurred in each cohort of n = 6 evaluable patients with AZD6738 160 mg BD and 240 mg BD (Days 1-14). According to the protocol, the maximum tolerated dose of AZD6738 is 240 mg BID (Days 1-14).

來自初始數據組，最普通的毒性（所有的起因、所有的級別）係厭食（n = 15，26%）、噁心（n = 15，26%）、白血球減少（n = 12，21%）和貧血（n = 11，19%）。51名患者係功效可評估的，並觀察到以下結果：1名完全反應（1.9%，黑色素瘤）、12名確定的部分反應（23.5%；2名胃癌，10名黑色素瘤，他們全部係在免疫療法後）、18名穩定疾病（35.3%）和20名疾病進展（39.2%）。來自劑量遞增的總確認反應率係25.5%。對黑色素瘤受試者觀察到的確定反應率（基於臨床研究者的評估）具體是30名患者中的10名或33.3%。From the initial data set, the most common toxicities (all causes, all grades) were anorexia (n = 15, 26%), nausea (n = 15, 26%), leukopenia (n = 12, 21%) and Anemia (n = 11, 19%). Fifty-one patients were evaluable for efficacy and the following outcomes were observed: 1 complete response (1.9%, melanoma), 12 confirmed partial responses (23.5%; 2 gastric cancer, 10 melanoma, all of whom were after immunotherapy), 18 had stable disease (35.3%), and 20 had progressive disease (39.2%). The overall confirmed response rate from dose escalation was 25.5%. The confirmed response rate (based on clinical investigator assessment) observed in subjects with melanoma was 10 out of 30 patients or 33.3%.

來自更新數據組，最普通的治療緊急不良事件（所有起因、所有級別）係貧血（n = 27，47%）和噬中性白血球減少症，包括嗜中性白血球計數減少（n = 24，42%）。不良事件的總結提供於表3中。在功效組中（57名接受至少一劑量的賽拉雷澤替博或紫杉醇的患者中），有1名完全反應（CR）（1.8%，黑色素瘤）、12名確定的部分反應（PR）（12/57 [21.1%]；2名胃癌、10名黑色素瘤，所有黑色素瘤病例都已經接受先前的免疫療法）、18名患者具有穩定疾病的最佳反應（SD，31.6%）、22名患者具有進行性疾病（PD）和4名不可評估的患者。在數據截取時，仍有三名患者正在接受研究藥物。在患有黑色素瘤的患者的亞組（n = 33）中，ORR係33.3%（95% CI，18.0 - 51.8）並且DCR係60.6%（95% CI 42.1 - 77.1%）。黑色素瘤患者的中值PFS係3.60個月（95% CI 2.00 - 5.78）、中值反應持續時間係9.9個月（95% CI 3.7 - 23.2）並且mOS係7.4個月（95% CI 5.7 - 11.9）。沒有出現基線水平的LDH相關的反應，因為在具有高基線LDH的患者中觀察到反應，在黑色素瘤中這係負的預後指標，表明即使在具有差的治療結果的該組中也有益處（來自LDH ＞ ULN的28人中有8名反應者）。也沒有出現PD-L1表現相關的反應（來自PD-L1表現 ≤ 5%的12人中有6名反應者）。而且，所有黑色素瘤的組織學亞型都觀察到反應，包括11名皮膚黑色素瘤中的3名、10名肢端黑色素瘤中的3名和11名黏膜黑色素瘤中的5名。對研究治療產生反應的黑色素瘤患者中的兩名對先前的PD-1免疫療法有反應；6名具有SD作為最佳反應並且3名具有PD作為最佳反應。From the updated data set, the most common treatment-emergent adverse events (all causes, all grades) were anemia (n = 27, 47%) and neutropenia, including decreased neutrophil counts (n = 24, 42 %). A summary of adverse events is provided in Table 3. In the efficacy group (among 57 patients who received at least one dose of xelarazepte or paclitaxel), there was 1 complete response (CR) (1.8%, melanoma), 12 confirmed partial responses (PR) (12/57 [21.1%]; 2 gastric cancer, 10 melanoma, all melanoma cases had received prior immunotherapy), 18 patients had best response with stable disease (SD, 31.6%), 22 Patients had progressive disease (PD) and 4 non-evaluable patients. At the time of data interception, three patients were still receiving study drug. In the subgroup of patients with melanoma (n = 33), ORR was 33.3% (95% CI, 18.0 - 51.8) and DCR was 60.6% (95% CI 42.1 - 77.1%). For melanoma patients, median PFS was 3.60 months (95% CI 2.00 - 5.78), median duration of response was 9.9 months (95% CI 3.7 - 23.2), and mOS was 7.4 months (95% CI 5.7 - 11.9) ). Baseline-level LDH-related responses did not occur, as responses were observed in patients with high baseline LDH, a negative prognostic indicator in melanoma, suggesting benefit even in this group with poor treatment outcomes (from 8 of 28 people with LDH > ULN were responders). There were also no responses related to PD-L1 performance (from 6 responders out of 12 with PD-L1 performance ≤ 5%). Furthermore, responses were observed in all histological subtypes of melanoma, including 3 of 11 cutaneous melanomas, 3 of 10 acral melanomas, and 5 of 11 mucosal melanomas. Two of the melanoma patients who responded to study treatment responded to prior PD-1 immunotherapy; 6 had SD as best response and 3 had PD as best response.

基線血漿的基因組分析（27名患者）顯示了在黑色素瘤患者中NF1體細胞突變和激活性NRAS突變的富集（分別是6/18和4/18）。在三名疾病控制的患者中觀察到白介素-12水平的週期性變化，這能反映反應機制的免疫學組分。Genomic analysis of baseline plasma (27 patients) showed enrichment for NF1 somatic mutations and activating NRAS mutations in melanoma patients (6/18 and 4/18, respectively). Cyclical changes in interleukin-12 levels, which could reflect the immunological component of the response mechanism, were observed in three disease-controlled patients.

圖2、3、4和5以圖形的形式呈現了臨床試驗數據的選擇。Figures 2, 3, 4 and 5 present a selection of clinical trial data in graphical form.

[表1A]：接受AZD6738（賽拉雷澤替博）和紫杉醇的黑色素瘤患者的臨床特徵 黑色素瘤患者（ N = 33 ）    先前的抗-PD(L)1/ 33（100.0） 先前的抗-CTLA4療法 0 先前的RAF抑制劑 6（18.1） 先前的化學療法線    1個方案 14（42.4） 2個方案 19（57.6） LDH表現    ≤ ULN 5（15.2） ＞ ULN至 ≤ 2x ULN 10（30.3） ＞ 2x ULN 18（54.5） 對先前的抗-PD1/L1的最佳反應    CR或PR 4（12.1） SD 16（48.5） PD 13（39.4） BRAF基因 3（9.0） NRAS基因 6（18.2） 腦轉移 3（9.0） 黑色素瘤亞型    肢端黑色素瘤 10（30.3） 皮膚黑色素瘤 11（33.3） 黏膜黑色素瘤 11（33.3） 未知 1（3.1） IV期黑色素瘤 33（100.0） [Table 1A]: Clinical characteristics of patients with melanoma who received AZD6738 (xirarazepate) and paclitaxel Melanoma patients ( N=33 ) previous anti-PD(L)1/ 33 (100.0) Prior anti-CTLA4 therapy 0 previous RAF inhibitor 6 (18.1) previous chemotherapy line 1 plan 14 (42.4) 2 options 19 (57.6) LDH performance ≤ ULN 5 (15.2) > ULN to ≤ 2x ULN 10 (30.3) > 2x ULN 18 (54.5) Optimal response to previous anti-PD1/L1 CR or PR 4 (12.1) SD 16 (48.5) PD 13 (39.4) BRAF gene 3 (9.0) NRAS gene 6 (18.2) brain metastases 3 (9.0) Melanoma subtypes Acral melanoma 10 (30.3) skin melanoma 11 (33.3) mucosal melanoma 11 (33.3) unknown 1 (3.1) Stage IV melanoma 33 (100.0)

[表1B]：接受AZD6738（賽拉雷澤替博）和紫杉醇的黑色素瘤患者反應者的臨床特徵    賽拉雷澤替博 + 紫杉醇 （總 n = 33 ；反應者 n = 11 ） 在IO難治患者中的反應 7名具有SD作為對先前IO的最佳反應 4名具有PD作為對先前IO的最佳反應 對先前PD-(L)1具有抗性的類型 原發性n = 19，其中5名反應（26%） 繼發性n = 7，其中4名反應（57%） 中止後n = 5，其中1名反應（20%） 不可評估n = 2，其中1名反應（50%），（不充分的藥物暴露） 所有3種黑色素瘤亞型中的反應 3名皮膚黑色素瘤 2名肢端黑色素瘤 5名黏膜黑色素瘤 1名未知 在具有高基線LDH的患者中的反應，差的預後指標 3名 ≤ ULN 5名 ＞ ULN並且 ≤ 2xULN 3名 ＞ 2xULN 在具有低PD-L1表現的患者中的反應（由研究者評估的） 11名中的6名PD-L1表現在0-5% 11名中的5名未知 腦轉移 沒有反應者具有腦轉移 肝轉移 17名中的4名（24%） 與BRAF、NRAS或KRAS狀態沒有明顯的聯繫 1名反應者具有BRAF突變 IO：免疫療法；SD：穩定疾病；PD：進行性疾病；PR：部分反應：LDH：乳酸脫氫酶；ULN：正常上限；根據SITC建議定義的原發性和繼發性抗性。[Table 1B]: Clinical characteristics of responders in melanoma patients who received AZD6738 (xirarazepate) and paclitaxel Sierra Rezetinib + Paclitaxel (total n = 33 ; responders n = 11 ) Response in IO-refractory patients 7 had SD as best response to prior IO 4 had PD as best response to prior IO Types that are resistant to previous PD-(L)1 Primary n = 19 with 5 responses (26%) Secondary n = 7 with 4 responses (57%) Post-discontinuation n = 5 with 1 response (20%) Not evaluable n = 2, 1 of them responded (50%), (inadequate drug exposure) Responses in all 3 melanoma subtypes 3 cutaneous melanomas 2 acral melanomas 5 mucosal melanomas 1 unknown Response in patients with high baseline LDH, poor prognostic indicator 3 ≤ ULN 5 > ULN and ≤ 2xULN 3 > 2xULN Response (Assessed by Investigator) in Patients with Low PD-L1 Performance 6 of 11 PD-L1 performance 0-5% 5 of 11 unknown brain metastases Non-responders have brain metastases liver metastases 4 of 17 (24%) No apparent link to BRAF, NRAS, or KRAS status 1 responder had a BRAF mutation IO: immunotherapy; SD: stable disease; PD: progressive disease; PR: partial response: LDH: lactate dehydrogenase; ULN: upper limit of normal; primary and secondary resistance as defined by SITC recommendations.

[表2]：在黑色素瘤患者中對先前的免疫療法具有原發性和繼發性抗性並反應於AZD6738（賽拉雷澤替博）與紫杉醇 原發性 繼發性 早期復發 中止後的 PD NE （不可評估的） 賽拉雷澤替博 + 紫杉醇 ORR DCR PFS OS 19 （ 58% ） 5（26%） 11（58%） 2.2 mo 7.2 mo 7 （ 21% ） 4（57%） 4（57%） 10.9 mo 25.5 mo N/A 5 （ 15% ） 2 （ 6% ） ORR：客觀反應率；DCR：疾病控制率；PFS：無進展存活；OS：總生存期；根據SITC建議定義的原發性和繼發性抗性。[Table 2]: Primary and secondary resistance to prior immunotherapy in patients with melanoma and response to AZD6738 (xirarazepate) and paclitaxel primary secondary Early recurrence PD after discontinuation NE (Non-evaluable) Sierra Rezetebo + Paclitaxel ORR DCR PFS OS 19 ( 58% ) 5 (26%) 11 (58%) 2.2 mo 7.2 mo 7 ( 21% ) 4 (57%) 4 (57%) 10.9 mo 25.5 mo N/A 5 ( 15% ) 2 ( 6% ) ORR: objective response rate; DCR: disease control rate; PFS: progression-free survival; OS: overall survival; primary and secondary resistance as defined by SITC recommendations.

[表3]：由CTCAE級別設定的安全性分析中在＞10%患者中發生的治療緊急不良事件 所有患者和劑量（ N = 57 ） 160 mg BD 黑色素瘤（ N = 6 ） 240 mg BD 黑色素瘤（ N = 9 ） 任何級別 n （ % ） ≥ 3 級 n （ % ） 任何級別 n （ % ） ≥ 3 級 n （ % ） 任何級別 n （ % ） ≥ 3 級 n （ % ） 具有任何 AE 的患者 57（100%） 28（49.1%） 6（100%） 4（67%） 5（56%） 5（56%） 貧血 27（47%） 13（23%） 5（83.3%） 3（50%） 2（22.2%） 2（22.2%） 噬中性白血球減少症和嗜中性白血球計數減少 24（42%） 17（30%） 4（83.3%） 4（67%） 5（56%） 5（56%） 厭食 17（30%） 0 2（33.3%） 0 2（22.2%） 0 噁心 17（30%） 1（2%） 2（33.3%） 0 3（33.3%） 0 脫髮 15（26%） 0 2（33.3%） 0 0 0 疲勞 10（17%） 0 1（17%） 0 3（33.3%） 0 血小板計數減少 & 血小板減少症 7（12%） 5（9%） 1（17%） 1（17%） 4（44.4%） 3（33.3%） 瘙癢 7（12%） 0 2（33.3%） 0 4（44.4） 0 嘔吐 7（12%） 1（2%） 1（17%） 0 2（22.2%） 0 皮疹 7（12%） 0 2（33.3%） 0 1（11.1%） 0 [Table 3]: Treatment-emergent adverse events in >10% of patients in safety analysis set by CTCAE class All patients and doses ( N=57 ) 160 mg BD Melanoma ( N=6 ) 240 mg BD melanoma ( N=9 ) any level n ( % ) ≥ Class 3 n ( % ) any level n ( % ) ≥ Class 3 n ( % ) any level n ( % ) ≥ Class 3 n ( % ) Patients with any AE 57 (100%) 28 (49.1%) 6 (100%) 4 (67%) 5 (56%) 5 (56%) anemia 27 (47%) 13 (23%) 5 (83.3%) 3 (50%) 2 (22.2%) 2 (22.2%) Neutropenia and decreased neutrophil count 24 (42%) 17 (30%) 4 (83.3%) 4 (67%) 5 (56%) 5 (56%) Anorexia 17 (30%) 0 2 (33.3%) 0 2 (22.2%) 0 nausea 17 (30%) 1 (2%) 2 (33.3%) 0 3 (33.3%) 0 hair loss 15 (26%) 0 2 (33.3%) 0 0 0 fatigue 10 (17%) 0 1 (17%) 0 3 (33.3%) 0 Thrombocytopenia & Thrombocytopenia 7 (12%) 5 (9%) 1 (17%) 1 (17%) 4 (44.4%) 3 (33.3%) itching 7 (12%) 0 2 (33.3%) 0 4 (44.4) 0 Vomit 7 (12%) 1 (2%) 1 (17%) 0 2 (22.2%) 0 rash 7 (12%) 0 2 (33.3%) 0 1 (11.1%) 0

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[圖1]：被設計以評估AZD6738的治療潛力的臨床試驗之研究設計。[Figure 1]: Study design of a clinical trial designed to evaluate the therapeutic potential of AZD6738.

[圖2]：在接受AZD6738和紫杉醇治療的患者的全分析組中，靶病變的總和中最佳%變化之瀑布圖。Y-軸代表根據RECIST v1.1標準評估的最大腫瘤減少%。M = 黑色素瘤。條柱由最佳總反應編碼。[Figure 2]: Waterfall plot of the best % change in the sum of target lesions in the full analysis group of patients treated with AZD6738 and paclitaxel. The Y-axis represents the maximum % tumor reduction assessed according to RECIST v1.1 criteria. M = melanoma. Bars are coded by best overall response.

[圖3]：顯示黑色素瘤患者反應於組合的AZD6738和紫杉醇治療之橫條圖。[FIG. 3]: Bar graph showing the response of melanoma patients to combined AZD6738 and paclitaxel treatment.

[圖4]：顯示AZD6738和紫杉醇治療黑色素瘤患者持續時間以及患者反應和ATM突變狀態之Swimmer圖。[Figure 4]: Swimmer plot showing the duration of treatment of melanoma patients with AZD6738 and paclitaxel as well as patient response and ATM mutation status.

[圖5]：顯示具有非進行性疾病（CR、PR、或SD）作為最佳反應的黑色素瘤患者的AZD6738和紫杉醇治療的持續時間之更新Swimmer圖。條柱由最佳反應編碼。[Figure 5]: Updated Swimmer plot showing duration of AZD6738 and paclitaxel treatment in melanoma patients with non-progressive disease (CR, PR, or SD) as the best response. Bars are coded by best response.

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Claims (28)

一種用於治療癌症的ATR抑制劑，其中該ATR抑制劑被投與至之前已經接受免疫療法的患者。An ATR inhibitor for the treatment of cancer, wherein the ATR inhibitor is administered to a patient who has previously received immunotherapy. 一種用於如請求項1所述使用的ATR抑制劑，其中該ATR抑制劑係AZD6738。An ATR inhibitor for use as claimed in claim 1, wherein the ATR inhibitor is AZD6738. 一種用於如請求項2所述使用的ATR抑制劑，其中該AZD6738在為期28天的週期的第1天至第14天投與。An ATR inhibitor for use as claimed in claim 2, wherein the AZD6738 is administered on days 1 to 14 of a 28 day cycle. 一種用於如請求項2或請求項3所述使用的ATR抑制劑，其中AZD6738的總日劑量為30 mg至500 mg。An ATR inhibitor for use as claimed in claim 2 or claim 3, wherein the total daily dose of AZD6738 is 30 mg to 500 mg. 一種用於如請求項2至4中任一項所述使用的ATR抑制劑，其中該AZD6738以240 mg劑量每日投與兩次。An ATR inhibitor for use as claimed in any one of claims 2 to 4, wherein the AZD6738 is administered at a dose of 240 mg twice daily. 一種用於如前述請求項中任一項所述使用的ATR抑制劑，其中該ATR抑制劑與紫杉烷組合投與。An ATR inhibitor for use as claimed in any preceding claim, wherein the ATR inhibitor is administered in combination with a taxane. 一種用於如請求項6所述使用的ATR抑制劑，其中該紫杉烷係紫杉醇。An ATR inhibitor for use as claimed in claim 6, wherein the taxane is paclitaxel. 一種用於如請求項6或請求項7所述使用的ATR抑制劑，其中該紫杉烷在為期28天的週期的第1天、第8天和第15天投與。An ATR inhibitor for use as claimed in claim 6 or claim 7, wherein the taxane is administered on days 1, 8 and 15 of a 28 day cycle. 一種用於如前述請求項中任一項所述使用的ATR抑制劑，其中該癌症選自黑色素瘤、胃癌、肉瘤、大腸癌、神經內分泌癌、肝細胞癌、非小細胞肺癌、以及鱗狀頭頸癌。An ATR inhibitor for use as described in any one of the preceding claims, wherein the cancer is selected from the group consisting of melanoma, gastric cancer, sarcoma, colorectal cancer, neuroendocrine cancer, hepatocellular carcinoma, non-small cell lung cancer, and squamous Head and neck cancer. 一種用於如前述請求項中任一項所述使用的ATR抑制劑，其中該癌症選自黑色素瘤和胃癌。An ATR inhibitor for use as claimed in any preceding claim, wherein the cancer is selected from melanoma and gastric cancer. 一種用於如請求項10所述使用的ATR抑制劑，其中該癌症係黑色素瘤。An ATR inhibitor for use as claimed in claim 10, wherein the cancer is melanoma. 一種用於如請求項11所述使用的ATR抑制劑，其中該癌症係皮膚黑色素瘤。An ATR inhibitor for use as claimed in claim 11, wherein the cancer is cutaneous melanoma. 一種用於如請求項11所述使用的ATR抑制劑，其中該癌症係肢端黑色素瘤。An ATR inhibitor for use as claimed in claim 11, wherein the cancer is acral melanoma. 一種用於如請求項11所述使用的ATR抑制劑，其中該癌症係黏膜黑色素瘤。An ATR inhibitor for use as claimed in claim 11, wherein the cancer is mucosal melanoma. 一種用於如前述請求項中任一項所述使用的ATR抑制劑，其中該癌症係ATM缺陷型。An ATR inhibitor for use as claimed in any preceding claim, wherein the cancer is ATM deficient. 一種用於如前述請求項中任一項所述使用的ATR抑制劑，其中該癌症係ARID1A缺陷型。An ATR inhibitor for use as claimed in any preceding claim, wherein the cancer is ARID1A deficient. 一種用於如前述請求項中任一項所述使用的ATR抑制劑，其中該免疫療法包括用免疫檢查點抑制劑治療。An ATR inhibitor for use as claimed in any preceding claim, wherein the immunotherapy comprises treatment with an immune checkpoint inhibitor. 一種用於如請求項17所述使用的ATR抑制劑，其中該免疫檢查點抑制劑選自PD-1抑制劑、PD-L1抑制劑和CTLA-4抑制劑。An ATR inhibitor for use as claimed in claim 17, wherein the immune checkpoint inhibitor is selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors and CTLA-4 inhibitors. 一種用於如請求項17所述使用的ATR抑制劑，其中該免疫檢查點抑制劑選自派姆單抗、納武單抗、西米普利單抗、斯巴達珠單抗、卡瑞利珠單抗、信迪利單抗、替雷利珠單抗、特瑞普利單抗、AMP-224、AMP-514、阿特珠單抗、阿維魯單抗、德瓦魯單抗、KN035、CK-301、AUNP12、CA-170、BMS-986189、伊匹單抗或曲美木單抗。An ATR inhibitor for use as claimed in claim 17, wherein the immune checkpoint inhibitor is selected from the group consisting of pembrolizumab, nivolumab, simipritimab, spartanizumab, carrex Lituzumab, sintilimab, tislelizumab, toripalizumab, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab , KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab or tremelimumab. 一種用於如前述請求項中任一項所述使用的ATR抑制劑，其中該患者對免疫療法具有原發性抗性。An ATR inhibitor for use as claimed in any preceding claim, wherein the patient is primary resistant to immunotherapy. 一種用於如請求項1至19中任一項所述使用的ATR抑制劑，其中該患者對免疫療法具有獲得性抗性。An ATR inhibitor for use as claimed in any one of claims 1 to 19, wherein the patient has acquired resistance to immunotherapy. 一種用於如前述請求項中任一項所述使用的ATR抑制劑，其中該治療取得大於30%的客觀反應率。An ATR inhibitor for use as claimed in any preceding claim, wherein the treatment achieves an objective response rate of greater than 30%. 一種用於如請求項1所述用於治療癌症的ATR抑制劑，其中該ATR抑制劑係AZD6738，其與紫杉烷組合被投與至之前已經接受用免疫檢查點抑制劑進行的療法的患者。An ATR inhibitor for use in the treatment of cancer as claimed in claim 1, wherein the ATR inhibitor is AZD6738, which is administered in combination with a taxane to a patient who has previously received therapy with an immune checkpoint inhibitor . 一種用於如請求項23所述用於治療癌症的ATR抑制劑，其中該ATR抑制劑係AZD6738，其與紫杉醇組合被投與至之前已經接受用免疫檢查點抑制劑進行的療法的黑色素瘤患者，該免疫檢查點抑制劑選自派姆單抗、納武單抗、西米普利單抗、斯巴達珠單抗、卡瑞利珠單抗、信迪利單抗、替雷利珠單抗、特瑞普利單抗、AMP-224、AMP-514、阿特珠單抗、阿維魯單抗、德瓦魯單抗、KN035、CK-301、AUNP12、CA-170、BMS-986189、伊匹單抗或曲美木單抗。An ATR inhibitor for use in the treatment of cancer as claimed in claim 23, wherein the ATR inhibitor is AZD6738, which is administered in combination with paclitaxel to melanoma patients who have previously received therapy with an immune checkpoint inhibitor , the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab, cimirizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab mAb, Toripalimab, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS- 986189, ipilimumab, or tremelimumab. 一種治療需要此種治療的人類或動物患者的癌症之方法，該方法包括將ATR抑制劑投與至之前已經接受免疫療法的患者。A method of treating cancer in a human or animal patient in need of such treatment, the method comprising administering an ATR inhibitor to a patient who has previously received immunotherapy. ATR抑制劑在製造用於治療癌症的藥物中之用途，其中該藥物被投與至之前已經接受免疫療法的患者。Use of an ATR inhibitor in the manufacture of a medicament for the treatment of cancer, wherein the medicament is administered to a patient who has previously received immunotherapy. 一種用於治療癌症的藥物組成物，該藥物組成物包含ATR抑制劑和藥學上可接受的賦形劑，其中該藥物組成物被投與至之前已經接受免疫療法的患者。A pharmaceutical composition for the treatment of cancer, the pharmaceutical composition comprising an ATR inhibitor and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is administered to a patient who has previously received immunotherapy. 一種套組，該套組包含含有ATR抑制劑和至少一種藥學上可接受的賦形劑的藥物組成物以及該藥物組成物在治療癌症中的使用說明書，其中該ATR抑制劑被投與至之前已經接受免疫療法的患者。A kit comprising a pharmaceutical composition containing an ATR inhibitor and at least one pharmaceutically acceptable excipient and an instruction for use of the pharmaceutical composition in the treatment of cancer, wherein the ATR inhibitor is administered to Patients who have already received immunotherapy.

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